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Roles and epigenetic regulation of epithelial–mesenchymal transition and its transcription factors in cancer initiation and progression

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Abstract

The epithelial–mesenchymal transition (EMT) is a crucial developmental process by which epithelial cells undergo a mesenchymal phenotypic change. During EMT, epigenetic mechanisms including DNA methylation and histone modifications are involved in the regulation of EMT-related genes. The epigenetic gene silencing of the epithelial marker E-cadherin has been well characterized. In particular, three major transcriptional repressors of E-cadherin, Snail, ZEB, and Twist families, also known as EMT-inducing transcription factors (EMT-TFs), play a crucial role in this process by cooperating with multiple epigenetic modifiers. Furthermore, recent studies have identified the novel epigenetic modifiers that control the expression of EMT-TFs, and these modifiers have emerged as critical regulators of cancer development and as novel therapeutic targets for human cancer. In this review, the diverse functions of EMT-TFs in cancer progression, the cooperative mechanisms of EMT-TFs with epigenetic modifiers, and epigenetic regulatory roles for the expression of EMT-TFs will be discussed.

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References

  1. Kalluri R, Weinberg RA (2009) The basics of epithelial–mesenchymal transition. J Clin Investig 119(6):1420–1428. doi:10.1172/JCI39104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial–mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007

    Article  CAS  PubMed  Google Scholar 

  3. Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454. doi:10.1038/nrc822

    Article  CAS  PubMed  Google Scholar 

  4. Ye X, Weinberg RA (2015) Epithelial–mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol 25(11):675–686. doi:10.1016/j.tcb.2015.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheel C, Weinberg RA (2012) Cancer stem cells and epithelial–mesenchymal transition: concepts and molecular links. Semin Cancer Biol 22(5–6):396–403. doi:10.1016/j.semcancer.2012.04.001

    Article  CAS  PubMed  Google Scholar 

  6. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715. doi:10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanchez-Tillo E, Liu Y, de Barrios O, Siles L, Fanlo L, Cuatrecasas M, Darling DS, Dean DC, Castells A, Postigo A (2012) EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell Mol Life Sci 69(20):3429–3456. doi:10.1007/s00018-012-1122-2

    Article  CAS  PubMed  Google Scholar 

  8. Smith BN, Bhowmick NA (2016) Role of EMT in metastasis and therapy resistance. J Clin Med. doi:10.3390/jcm5020017

    Google Scholar 

  9. Hill RP, Marie-Egyptienne DT, Hedley DW (2009) Cancer stem cells, hypoxia and metastasis. Semin Radiat Oncol 19(2):106–111. doi:10.1016/j.semradonc.2008.12.002

    Article  PubMed  Google Scholar 

  10. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7(6):415–428. doi:10.1038/nrc2131

    Article  CAS  PubMed  Google Scholar 

  11. Bedi U, Mishra VK, Wasilewski D, Scheel C, Johnsen SA (2014) Epigenetic plasticity: a central regulator of epithelial-to-mesenchymal transition in cancer. Oncotarget 5(8):2016–2029

    Article  PubMed  PubMed Central  Google Scholar 

  12. De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110. doi:10.1038/nrc3447

    Article  PubMed  CAS  Google Scholar 

  13. Tam WL, Weinberg RA (2013) The epigenetics of epithelial–mesenchymal plasticity in cancer. Nat Med 19(11):1438–1449. doi:10.1038/nm.3336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kiesslich T, Pichler M, Neureiter D (2013) Epigenetic control of epithelial–mesenchymal-transition in human cancer. Mol Clin Oncol 1(1):3–11. doi:10.3892/mco.2012.28

    PubMed  Google Scholar 

  15. Dawson MA, Kouzarides T (2012) Cancer epigenetics: from mechanism to therapy. Cell 150(1):12–27. doi:10.1016/j.cell.2012.06.013

    Article  CAS  PubMed  Google Scholar 

  16. Jones PA, Baylin SB (2007) The epigenomics of cancer. Cell 128(4):683–692. doi:10.1016/j.cell.2007.01.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lin Y, Wu Y, Li J, Dong C, Ye X, Chi YI, Evers BM, Zhou BP (2010) The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase 1. EMBO J 29(11):1803–1816. doi:10.1038/emboj.2010.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dong C, Wu Y, Yao J, Wang Y, Yu Y, Rychahou PG, Evers BM, Zhou BP (2012) G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J Clin Investig 122(4):1469–1486. doi:10.1172/JCI57349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang F, Sun L, Li Q, Han X, Lei L, Zhang H, Shang Y (2012) SET8 promotes epithelial–mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J 31(1):110–123. doi:10.1038/emboj.2011.364

    Article  CAS  PubMed  Google Scholar 

  20. Cho MH, Park JH, Choi HJ, Park MK, Won HY, Park YJ, Lee CH, Oh SH, Song YS, Kim HS, Oh YH, Lee JY, Kong G (2015) DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression. Nat Commun 6:7821. doi:10.1038/ncomms8821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Choi HJ, Park JH, Park M, Won HY, Joo HS, Lee CH, Lee JY, Kong G (2015) UTX inhibits EMT-induced breast CSC properties by epigenetic repression of EMT genes in cooperation with LSD1 and HDAC1. EMBO Rep 16(10):1288–1298. doi:10.15252/embr.201540244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D (2015) Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527(7579):472–476. doi:10.1038/nature15748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R (2015) Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527(7579):525–530. doi:10.1038/nature16064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Markiewicz A, Ahrends T, Welnicka-Jaskiewicz M, Seroczynska B, Skokowski J, Jaskiewicz J, Szade J, Biernat W, Zaczek AJ (2012) Expression of epithelial to mesenchymal transition-related markers in lymph node metastases as a surrogate for primary tumor metastatic potential in breast cancer. J Transl Med 10:226. doi:10.1186/1479-5876-10-226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shin NR, Jeong EH, Choi CI, Moon HJ, Kwon CH, Chu IS, Kim GH, Jeon TY, Kim DH, Lee JH, do Park Y (2012) Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer. BMC Cancer 12:521. doi:10.1186/1471-2407-12-521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Forghanifard MM, Moaven O, Farshchian M, Montazer M, Raeisossadati R, Abdollahi A, Moghbeli M, Nejadsattari T, Parivar K, Abbaszadegan MR (2012) Expression analysis elucidates the roles of MAML1 and Twist1 in esophageal squamous cell carcinoma aggressiveness and metastasis. Ann Surg Oncol 19(3):743–749. doi:10.1245/s10434-011-2074-8

    Article  PubMed  Google Scholar 

  27. Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A, Soini Y (2013) Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: association with an aggressive tumour phenotype. Breast Cancer Res Treat 138(1):81–90. doi:10.1007/s10549-013-2442-0

    Article  CAS  PubMed  Google Scholar 

  28. Pena C, Garcia JM, Silva J, Garcia V, Rodriguez R, Alonso I, Millan I, Salas C, de Herreros AG, Munoz A, Bonilla F (2005) E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. Hum Mol Genet 14(22):3361–3370. doi:10.1093/hmg/ddi366

    Article  CAS  PubMed  Google Scholar 

  29. Elloul S, Elstrand MB, Nesland JM, Trope CG, Kvalheim G, Goldberg I, Reich R, Davidson B (2005) Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103(8):1631–1643. doi:10.1002/cncr.20946

    Article  CAS  PubMed  Google Scholar 

  30. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A (2000) The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2(2):84–89. doi:10.1038/35000034

    Article  CAS  PubMed  Google Scholar 

  31. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA (2000) The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2(2):76–83. doi:10.1038/35000025

    Article  CAS  PubMed  Google Scholar 

  32. Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A (2003) The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci 116(Pt 3):499–511

    Article  CAS  PubMed  Google Scholar 

  33. Hajra KM, Chen DY, Fearon ER (2002) The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62(6):1613–1618

    CAS  PubMed  Google Scholar 

  34. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24(14):2375–2385. doi:10.1038/sj.onc.1208429

    Article  CAS  PubMed  Google Scholar 

  35. Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7(6):1267–1278

    Article  CAS  PubMed  Google Scholar 

  36. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117(7):927–939. doi:10.1016/j.cell.2004.06.006

    Article  CAS  PubMed  Google Scholar 

  37. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, Cano A (2001) A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J Biol Chem 276(29):27424–27431. doi:10.1074/jbc.M100827200

    Article  CAS  PubMed  Google Scholar 

  38. Postigo AA, Dean DC (1999) Independent repressor domains in ZEB regulate muscle and T-cell differentiation. Mol Cell Biol 19(12):7961–7971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang SM, Coljee VW, Pignolo RJ, Rotenberg MO, Cristofalo VJ, Sierra F (1997) Cloning of the human twist gene: its expression is retained in adult mesodermally-derived tissues. Gene 187(1):83–92

    Article  CAS  PubMed  Google Scholar 

  40. Oshima A, Tanabe H, Yan T, Lowe GN, Glackin CA, Kudo A (2002) A novel mechanism for the regulation of osteoblast differentiation: transcription of periostin, a member of the fasciclin I family, is regulated by the bHLH transcription factor, twist. J Cell Biochem 86(4):792–804. doi:10.1002/jcb.10272

    Article  CAS  PubMed  Google Scholar 

  41. Mauhin V, Lutz Y, Dennefeld C, Alberga A (1993) Definition of the DNA-binding site repertoire for the Drosophila transcription factor SNAIL. Nucleic Acids Res 21(17):3951–3957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fujiwara S, Corbo JC, Levine M (1998) The snail repressor establishes a muscle/notochord boundary in the Ciona embryo. Development 125(13):2511–2520

    CAS  PubMed  Google Scholar 

  43. McCoy EL, Iwanaga R, Jedlicka P, Abbey NS, Chodosh LA, Heichman KA, Welm AL, Ford HL (2009) Six1 expands the mouse mammary epithelial stem/progenitor cell pool and induces mammary tumors that undergo epithelial–mesenchymal transition. J Clin Invest 119(9):2663–2677. doi:10.1172/JCI37691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA (2011) Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145(6):926–940. doi:10.1016/j.cell.2011.04.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hollier BG, Tinnirello AA, Werden SJ, Evans KW, Taube JH, Sarkar TR, Sphyris N, Shariati M, Kumar SV, Battula VL, Herschkowitz JI, Guerra R, Chang JT, Miura N, Rosen JM, Mani SA (2013) FOXC2 expression links epithelial–mesenchymal transition and stem cell properties in breast cancer. Cancer Res 73(6):1981–1992. doi:10.1158/0008-5472.CAN-12-2962

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26(17):2813–2820. doi:10.1200/JCO.2008.16.3931

    Article  PubMed  PubMed Central  Google Scholar 

  47. Marotta LL, Polyak K (2009) Cancer stem cells: a model in the making. Curr Opin Genet Dev 19(1):44–50. doi:10.1016/j.gde.2008.12.003

    Article  PubMed  CAS  Google Scholar 

  48. Chakrabarti R, Hwang J, Andres Blanco M, Wei Y, Lukacisin M, Romano RA, Smalley K, Liu S, Yang Q, Ibrahim T, Mercatali L, Amadori D, Haffty BG, Sinha S, Kang Y (2012) Elf5 inhibits the epithelial–mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. Nat Cell Biol 14(11):1212–1222. doi:10.1038/ncb2607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. DiMeo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, Kuperwasser C (2009) A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial–mesenchymal transition in basal-like breast cancer. Cancer Res 69(13):5364–5373. doi:10.1158/0008-5472.CAN-08-4135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749. doi:10.1038/nrc1694

    Article  CAS  PubMed  Google Scholar 

  51. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS One 3(8):e2888. doi:10.1371/journal.pone.0002888

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Morel AP, Hinkal GW, Thomas C, Fauvet F, Courtois-Cox S, Wierinckx A, Devouassoux-Shisheboran M, Treilleux I, Tissier A, Gras B, Pourchet J, Puisieux I, Browne GJ, Spicer DB, Lachuer J, Ansieau S, Puisieux A (2012) EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genet 8(5):e1002723. doi:10.1371/journal.pgen.1002723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ansieau S, Bastid J, Doreau A, Morel AP, Bouchet BP, Thomas C, Fauvet F, Puisieux I, Doglioni C, Piccinin S, Maestro R, Voeltzel T, Selmi A, Valsesia-Wittmann S, Caron de Fromentel C, Puisieux A (2008) Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14(1):79–89. doi:10.1016/j.ccr.2008.06.005

    Article  CAS  PubMed  Google Scholar 

  54. Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M (2009) Role of Ras signaling in the induction of snail by transforming growth factor-beta. J Biol Chem 284(1):245–253. doi:10.1074/jbc.M804777200

    Article  CAS  PubMed  Google Scholar 

  55. Ohashi S, Natsuizaka M, Wong GS, Michaylira CZ, Grugan KD, Stairs DB, Kalabis J, Vega ME, Kalman RA, Nakagawa M, Klein-Szanto AJ, Herlyn M, Diehl JA, Rustgi AK, Nakagawa H (2010) Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res 70(10):4174–4184. doi:10.1158/0008-5472.CAN-09-4614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu Y, Sanchez-Tillo E, Lu X, Huang L, Clem B, Telang S, Jenson AB, Cuatrecasas M, Chesney J, Postigo A, Dean DC (2013) Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression. J Biol Chem 288(16):11572–11580. doi:10.1074/jbc.M112.434951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, Brunton VG, Morton J, Sansom O, Schuler J, Stemmler MP, Herzberger C, Hopt U, Keck T, Brabletz S, Brabletz T (2009) The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 11(12):1487–1495. doi:10.1038/ncb1998

    Article  CAS  PubMed  Google Scholar 

  58. Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, Huang CH, Kao SY, Tzeng CH, Tai SK, Chang SY, Lee OK, Wu KJ (2010) Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nat Cell Biol 12(10):982–992. doi:10.1038/ncb2099

    Article  PubMed  CAS  Google Scholar 

  59. Cho KB, Cho MK, Lee WY, Kang KW (2010) Overexpression of c-myc induces epithelial mesenchymal transition in mammary epithelial cells. Cancer Lett 293(2):230–239. doi:10.1016/j.canlet.2010.01.013

    Article  CAS  PubMed  Google Scholar 

  60. Smith AP, Verrecchia A, Faga G, Doni M, Perna D, Martinato F, Guccione E, Amati B (2009) A positive role for Myc in TGFbeta-induced Snail transcription and epithelial-to-mesenchymal transition. Oncogene 28(3):422–430. doi:10.1038/onc.2008.395

    Article  CAS  PubMed  Google Scholar 

  61. Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y, Miyazaki K (2004) Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer 90(6):1265–1273. doi:10.1038/sj.bjc.6601685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yokoyama K, Kamata N, Fujimoto R, Tsutsumi S, Tomonari M, Taki M, Hosokawa H, Nagayama M (2003) Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas. Int J Oncol 22(4):891–898

    CAS  PubMed  Google Scholar 

  63. Olmeda D, Jorda M, Peinado H, Fabra A, Cano A (2007) Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene 26(13):1862–1874. doi:10.1038/sj.onc.1209997

    Article  CAS  PubMed  Google Scholar 

  64. Kudo-Saito C, Shirako H, Takeuchi T, Kawakami Y (2009) Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 15(3):195–206. doi:10.1016/j.ccr.2009.01.023

    Article  CAS  PubMed  Google Scholar 

  65. Shih JY, Tsai MF, Chang TH, Chang YL, Yuan A, Yu CJ, Lin SB, Liou GY, Lee ML, Chen JJ, Hong TM, Yang SC, Su JL, Lee YC, Yang PC (2005) Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients with lung adenocarcinoma. Clin Cancer Res 11(22):8070–8078. doi:10.1158/1078-0432.CCR-05-0687

    Article  CAS  PubMed  Google Scholar 

  66. Tanno B, Sesti F, Cesi V, Bossi G, Ferrari-Amorotti G, Bussolari R, Tirindelli D, Calabretta B, Raschella G (2010) Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin. J Biol Chem 285(38):29434–29445. doi:10.1074/jbc.M109.089045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Spaderna S, Schmalhofer O, Wahlbuhl M, Dimmler A, Bauer K, Sultan A, Hlubek F, Jung A, Strand D, Eger A, Kirchner T, Behrens J, Brabletz T (2008) The transcriptional repressor ZEB1 promotes metastasis and loss of cell polarity in cancer. Cancer Res 68(2):537–544. doi:10.1158/0008-5472.CAN-07-5682

    Article  CAS  PubMed  Google Scholar 

  68. Zhang P, Sun Y, Ma L (2015) ZEB1: at the crossroads of epithelial–mesenchymal transition, metastasis and therapy resistance. Cell Cycle 14(4):481–487. doi:10.1080/15384101.2015.1006048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Meng F, Wu G (2012) The rejuvenated scenario of epithelial–mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 31(3–4):455–467. doi:10.1007/s10555-012-9379-3

    Article  CAS  PubMed  Google Scholar 

  70. Mimeault M, Batra SK (2013) Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J Cell Mol Med 17(1):30–54. doi:10.1111/jcmm.12004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wu CY, Tsai YP, Wu MZ, Teng SC, Wu KJ (2012) Epigenetic reprogramming and post-transcriptional regulation during the epithelial–mesenchymal transition. Trends Genet 28(9):454–463. doi:10.1016/j.tig.2012.05.005

    Article  CAS  PubMed  Google Scholar 

  72. Salnikov AV, Liu L, Platen M, Gladkich J, Salnikova O, Ryschich E, Mattern J, Moldenhauer G, Werner J, Schemmer P, Buchler MW, Herr I (2012) Hypoxia induces EMT in low and highly aggressive pancreatic tumor cells but only cells with cancer stem cell characteristics acquire pronounced migratory potential. PLoS One 7(9):e46391. doi:10.1371/journal.pone.0046391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X, Dong J, Qian C (2013) Hypoxia induces epithelial–mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma. BMC Cancer 13:108. doi:10.1186/1471-2407-13-108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Sun S, Ning X, Zhang Y, Lu Y, Nie Y, Han S, Liu L, Du R, Xia L, He L, Fan D (2009) Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int 75(12):1278–1287. doi:10.1038/ki.2009.62

    Article  CAS  PubMed  Google Scholar 

  75. Luo Y, He DL, Ning L, Shen SL, Li L, Li X (2006) Hypoxia-inducible factor-1alpha induces the epithelial–mesenchymal transition of human prostatecancer cells. Chin Med J 119(9):713–718

    CAS  PubMed  Google Scholar 

  76. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305. doi:10.1038/ncb1691

    Article  CAS  PubMed  Google Scholar 

  77. Yang MH, Wu KJ (2008) TWIST activation by hypoxia inducible factor-1 (HIF-1): implications in metastasis and development. Cell Cycle 7(14):2090–2096

    Article  CAS  PubMed  Google Scholar 

  78. Zhang W, Shi X, Peng Y, Wu M, Zhang P, Xie R, Wu Y, Yan Q, Liu S, Wang J (2015) HIF-1alpha promotes epithelial–mesenchymal transition and metastasis through direct regulation of ZEB1 in colorectal cancer. PLoS One 10(6):e0129603. doi:10.1371/journal.pone.0129603

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. van den Beucken T, Koch E, Chu K, Rupaimoole R, Prickaerts P, Adriaens M, Voncken JW, Harris AL, Buffa FM, Haider S, Starmans MH, Yao CQ, Ivan M, Ivan C, Pecot CV, Boutros PC, Sood AK, Koritzinsky M, Wouters BG (2014) Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER. Nat Commun 5:5203. doi:10.1038/ncomms6203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Liu L, Tong Q, Liu S, Cui J, Zhang Q, Sun W, Yang S (2016) ZEB1 upregulates VEGF expression and stimulates angiogenesis in breast cancer. PLoS One 11(2):e0148774. doi:10.1371/journal.pone.0148774

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Inuzuka T, Tsuda M, Tanaka S, Kawaguchi H, Higashi Y, Ohba Y (2009) Integral role of transcription factor 8 in the negative regulation of tumor angiogenesis. Cancer Res 69(4):1678–1684. doi:10.1158/0008-5472.CAN-08-3620

    Article  CAS  PubMed  Google Scholar 

  82. Peinado H, Marin F, Cubillo E, Stark HJ, Fusenig N, Nieto MA, Cano A (2004) Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117(Pt 13):2827–2839. doi:10.1242/jcs.01145

    Article  CAS  PubMed  Google Scholar 

  83. Low-Marchelli JM, Ardi VC, Vizcarra EA, van Rooijen N, Quigley JP, Yang J (2013) Twist1 induces CCL2 and recruits macrophages to promote angiogenesis. Cancer Res 73(2):662–671. doi:10.1158/0008-5472.CAN-12-0653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hu L, Roth JM, Brooks P, Ibrahim S, Karpatkin S (2008) Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Res 68(11):4296–4302. doi:10.1158/0008-5472.CAN-08-0067

    Article  CAS  PubMed  Google Scholar 

  85. Niu RF, Zhang L, Xi GM, Wei XY, Yang Y, Shi YR, Hao XS (2007) Up-regulation of Twist induces angiogenesis and correlates with metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 26(3):385–394

    CAS  PubMed  Google Scholar 

  86. Mironchik Y, Winnard PT Jr, Vesuna F, Kato Y, Wildes F, Pathak AP, Kominsky S, Artemov D, Bhujwalla Z, Van Diest P, Burger H, Glackin C, Raman V (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65(23):10801–10809. doi:10.1158/0008-5472.CAN-05-0712

    Article  CAS  PubMed  Google Scholar 

  87. Chen HF, Huang CH, Liu CJ, Hung JJ, Hsu CC, Teng SC, Wu KJ (2014) Twist1 induces endothelial differentiation of tumour cells through the Jagged1-KLF4 axis. Nat Commun 5:4697. doi:10.1038/ncomms5697

    Article  CAS  PubMed  Google Scholar 

  88. Luo M, Brooks M, Wicha MS (2015) Epithelial–mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance. Curr Pharm Des 21(10):1301–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sui H, Zhu L, Deng W, Li Q (2014) Epithelial–mesenchymal transition and drug resistance: role, molecular mechanisms, and therapeutic strategies. Oncol Res Treat 37(10):584–589. doi:10.1159/000367802

    Article  CAS  PubMed  Google Scholar 

  90. Shang Y, Cai X, Fan D (2013) Roles of epithelial–mesenchymal transition in cancer drug resistance. Curr Cancer Drug Targets 13(9):915–929

    Article  CAS  PubMed  Google Scholar 

  91. Tryndyak VP, Beland FA, Pogribny IP (2010) E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer 126(11):2575–2583. doi:10.1002/ijc.24972

    CAS  PubMed  Google Scholar 

  92. Li QQ, Xu JD, Wang WJ, Cao XX, Chen Q, Tang F, Chen ZQ, Liu XP, Xu ZD (2009) Twist1-mediated adriamycin-induced epithelial–mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res 15(8):2657–2665. doi:10.1158/1078-0432.CCR-08-2372

    Article  CAS  PubMed  Google Scholar 

  93. Khan MA, Chen HC, Zhang D, Fu J (2013) Twist: a molecular target in cancer therapeutics. Tumour Biol 34(5):2497–2506. doi:10.1007/s13277-013-1002-x

    Article  CAS  PubMed  Google Scholar 

  94. Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH (2007) Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res 67(5):1979–1987. doi:10.1158/0008-5472.CAN-06-1479

    Article  CAS  PubMed  Google Scholar 

  95. Zhang X, Wang Q, Ling MT, Wong YC, Leung SC, Wang X (2007) Anti-apoptotic role of TWIST and its association with Akt pathway in mediating taxol resistance in nasopharyngeal carcinoma cells. Int J Cancer 120(9):1891–1898. doi:10.1002/ijc.22489

    Article  CAS  PubMed  Google Scholar 

  96. Wang X, Ling MT, Guan XY, Tsao SW, Cheung HW, Lee DT, Wong YC (2004) Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene 23(2):474–482. doi:10.1038/sj.onc.1207128

    Article  PubMed  CAS  Google Scholar 

  97. Dong P, Kaneuchi M, Xiong Y, Cao L, Cai M, Liu X, Guo SW, Ju J, Jia N, Konno Y, Watari H, Hosaka M, Sudo S, Sakuragi N (2014) Identification of KLF17 as a novel epithelial to mesenchymal transition inducer via direct activation of TWIST1 in endometrioid endometrial cancer. Carcinogenesis 35(4):760–768. doi:10.1093/carcin/bgt369

    Article  CAS  PubMed  Google Scholar 

  98. Pham CG, Bubici C, Zazzeroni F, Knabb JR, Papa S, Kuntzen C, Franzoso G (2007) Upregulation of Twist-1 by NF-kappaB blocks cytotoxicity induced by chemotherapeutic drugs. Mol Cell Biol 27(11):3920–3935. doi:10.1128/MCB.01219-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Deng JJ, Zhang W, Xu XM, Zhang F, Tao WP, Ye JJ, Ge W (2016) Twist mediates an aggressive phenotype in human colorectal cancer cells. Int J Oncol 48(3):1117–1124. doi:10.3892/ijo.2016.3342

    PubMed  Google Scholar 

  100. Wang H, Zhang G, Zhang H, Zhang F, Zhou B, Ning F, Wang HS, Cai SH, Du J (2014) Acquisition of epithelial–mesenchymal transition phenotype and cancer stem cell-like properties in cisplatin-resistant lung cancer cells through AKT/beta-catenin/Snail signaling pathway. Eur J Pharmacol 723:156–166. doi:10.1016/j.ejphar.2013.12.004

    Article  CAS  PubMed  Google Scholar 

  101. Haslehurst AM, Koti M, Dharsee M, Nuin P, Evans K, Geraci J, Childs T, Chen J, Li J, Weberpals J, Davey S, Squire J, Park PC, Feilotter H (2012) EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer. BMC Cancer 12:91. doi:10.1186/1471-2407-12-91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kwok WK, Ling MT, Lee TW, Lau TC, Zhou C, Zhang X, Chua CW, Chan KW, Chan FL, Glackin C, Wong YC, Wang X (2005) Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res 65(12):5153–5162. doi:10.1158/0008-5472.CAN-04-3785

    Article  CAS  PubMed  Google Scholar 

  103. Zhu X, Shen H, Yin X, Long L, Xie C, Liu Y, Hui L, Lin X, Fang Y, Cao Y, Xu Y, Li M, Xu W, Li Y (2016) miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin. Oncogene 35(3):323–332. doi:10.1038/onc.2015.84

    Article  CAS  PubMed  Google Scholar 

  104. Sayan AE, Griffiths TR, Pal R, Browne GJ, Ruddick A, Yagci T, Edwards R, Mayer NJ, Qazi H, Goyal S, Fernandez S, Straatman K, Jones GD, Bowman KJ, Colquhoun A, Mellon JK, Kriajevska M, Tulchinsky E (2009) SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proc Natl Acad Sci USA 106(35):14884–14889. doi:10.1073/pnas.0902042106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yoshida T, Song L, Bai Y, Kinose F, Li J, Ohaegbulam KC, Munoz-Antonia T, Qu X, Eschrich S, Uramoto H, Tanaka F, Nasarre P, Gemmill RM, Roche J, Drabkin HA, Haura EB (2016) ZEB1 mediates acquired resistance to the epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer. PLoS One 11(1):e0147344. doi:10.1371/journal.pone.0147344

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Haddad Y, Choi W, McConkey DJ (2009) Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin Cancer Res 15(2):532–542. doi:10.1158/1078-0432.CCR-08-1733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Witta SE, Gemmill RM, Hirsch FR, Coldren CD, Hedman K, Ravdel L, Helfrich B, Dziadziuszko R, Chan DC, Sugita M, Chan Z, Baron A, Franklin W, Drabkin HA, Girard L, Gazdar AF, Minna JD, Bunn PA Jr (2006) Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 66(2):944–950. doi:10.1158/0008-5472.CAN-05-1988

    Article  CAS  PubMed  Google Scholar 

  108. Sato F, Kubota Y, Natsuizaka M, Maehara O, Hatanaka Y, Marukawa K, Terashita K, Suda G, Ohnishi S, Shimizu Y, Komatsu Y, Ohashi S, Kagawa S, Kinugasa H, Whelan KA, Nakagawa H, Sakamoto N (2015) EGFR inhibitors prevent induction of cancer stem-like cells in esophageal squamous cell carcinoma by suppressing epithelial–mesenchymal transition. Cancer Biol Ther 16(6):933–940. doi:10.1080/15384047.2015.1040959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chang TH, Tsai MF, Su KY, Wu SG, Huang CP, Yu SL, Yu YL, Lan CC, Yang CH, Lin SB, Wu CP, Shih JY, Yang PC (2011) Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. Am J Respir Crit Care Med 183(8):1071–1079. doi:10.1164/rccm.201009-1440OC

    Article  CAS  PubMed  Google Scholar 

  110. Liu H, Zhang HW, Sun XF, Guo XH, He YN, Cui SD, Fan QX (2013) Tamoxifen-resistant breast cancer cells possess cancer stem-like cell properties. Chin Med J 126(16):3030–3034

    CAS  PubMed  Google Scholar 

  111. Vesuna F, Lisok A, Kimble B, Domek J, Kato Y, van der Groep P, Artemov D, Kowalski J, Carraway H, van Diest P, Raman V (2012) Twist contributes to hormone resistance in breast cancer by downregulating estrogen receptor-alpha. Oncogene 31(27):3223–3234. doi:10.1038/onc.2011.483

    Article  CAS  PubMed  Google Scholar 

  112. Scherbakov AM, Andreeva OE, Shatskaya VA, Krasil’nikov MA (2012) The relationships between snail1 and estrogen receptor signaling in breast cancer cells. J Cell Biochem 113(6):2147–2155. doi:10.1002/jcb.24087

    Article  CAS  PubMed  Google Scholar 

  113. Manavalan TT, Teng Y, Litchfield LM, Muluhngwi P, Al-Rayyan N, Klinge CM (2013) Reduced expression of miR-200 family members contributes to antiestrogen resistance in LY2 human breast cancer cells. PLoS One 8(4):e62334. doi:10.1371/journal.pone.0062334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Oliveras-Ferraros C, Corominas-Faja B, Cufi S, Vazquez-Martin A, Martin-Castillo B, Iglesias JM, Lopez-Bonet E, Martin AG, Menendez JA (2012) Epithelial-to-mesenchymal transition (EMT) confers primary resistance to trastuzumab (Herceptin). Cell Cycle 11(21):4020–4032. doi:10.4161/cc.22225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16(4):168–174

    Article  CAS  PubMed  Google Scholar 

  116. Jones PL, Wolffe AP (1999) Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol 9(5):339–347. doi:10.1006/scbi.1999.0134

  117. Bhutani N, Burns DM, Blau HM (2011) DNA demethylation dynamics. Cell 146(6):866–872. doi:10.1016/j.cell.2011.08.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Tsai YP, Chen HF, Chen SY, Cheng WC, Wang HW, Shen ZJ, Song C, Teng SC, He C, Wu KJ (2014) TET1 regulates hypoxia-induced epithelial–mesenchymal transition by acting as a co-activator. Genome Biol 15(12):513. doi:10.1186/s13059-014-0513-0

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Berger SL (2007) The complex language of chromatin regulation during transcription. Nat 447(7143):407–412. doi:10.1038/nature05915

  120. Varier RA, Timmers HT (2011) Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta 1815(1):75–89. doi:10.1016/j.bbcan.2010.10.002

  121. McDonald OG, Wu H, Timp W, Doi A, Feinberg AP (2011) Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition. Nat Struct Mol Biol 18(8):867–874. doi:10.1038/nsmb.2084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ke XS, Qu Y, Cheng Y, Li WC, Rotter V, Oyan AM, Kalland KH (2010) Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells. BMC Genom 11:669. doi:10.1186/1471-2164-11-669

    Article  CAS  Google Scholar 

  123. Wang Y, Shang Y (2013) Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res 319(2):160–169. doi:10.1016/j.yexcr.2012.07.019

    Article  CAS  PubMed  Google Scholar 

  124. Graff JR, Herman JG, Lapidus RG, Chopra H, Xu R, Jarrard DF, Isaacs WB, Pitha PM, Davidson NE, Baylin SB (1995) E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas. Cancer Res 55(22):5195–5199

    CAS  PubMed  Google Scholar 

  125. Peinado H, Ballestar E, Esteller M, Cano A (2004) Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol 24(1):306–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Sun L, Kokura K, Izumi V, Koomen JM, Seto E, Chen J, Fang J (2015) MPP8 and SIRT1 crosstalk in E-cadherin gene silencing and epithelial–mesenchymal transition. EMBO Rep 16(6):689–699. doi:10.15252/embr.201439792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kim HY, Park JH, Won HY, Lee JY, Kong G (2015) CBX7 inhibits breast tumorigenicity through DKK-1-mediated suppression of the Wnt/beta-catenin pathway. FASEB J 29(1):300–313. doi:10.1096/fj.14-253997

    Article  CAS  PubMed  Google Scholar 

  128. Kim NH, Kim SN, Kim YK (2011) Involvement of HDAC1 in E-cadherin expression in prostate cancer cells; its implication for cell motility and invasion. Biochem Biophys Res Commun 404(4):915–921. doi:10.1016/j.bbrc.2010.12.081

    Article  CAS  PubMed  Google Scholar 

  129. Dong C, Wu Y, Wang Y, Wang C, Kang T, Rychahou PG, Chi YI, Evers BM, Zhou BP (2013) Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32(11):1351–1362. doi:10.1038/onc.2012.169

    Article  CAS  PubMed  Google Scholar 

  130. Lin Y, Dong C, Zhou BP (2014) Epigenetic regulation of EMT: the Snail story. Curr Pharm Des 20(11):1698–1705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lin T, Ponn A, Hu X, Law BK, Lu J (2010) Requirement of the histone demethylase LSD1 in Snai1-mediated transcriptional repression during epithelial–mesenchymal transition. Oncogene 29(35):4896–4904. doi:10.1038/onc.2010.234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Malouf GG, Taube JH, Lu Y, Roysarkar T, Panjarian S, Estecio MR, Jelinek J, Yamazaki J, Raynal NJ, Long H, Tahara T, Tinnirello A, Ramachandran P, Zhang XY, Liang S, Mani SA, Issa JP (2013) Architecture of epigenetic reprogramming following Twist1-mediated epithelial–mesenchymal transition. Genome Biol 14(12):R144. doi:10.1186/gb-2013-14-12-r144

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, Escriva M, Hernandez-Munoz I, Di Croce L, Helin K, Garcia de Herreros A, Peiro S (2008) Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol 28(15):4772–4781. doi:10.1128/MCB.00323-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Yao R, Jiang H, Ma Y, Wang L, Wang L, Du J, Hou P, Gao Y, Zhao L, Wang G, Zhang Y, Liu DX, Huang B, Lu J (2014) PRMT7 induces epithelial-to-mesenchymal transition and promotes metastasis in breast cancer. Cancer Res 74(19):5656–5667. doi:10.1158/0008-5472.CAN-14-0800

    Article  CAS  PubMed  Google Scholar 

  135. Kidder BL, Palmer S, Knott JG (2009) SWI/SNF-Brg1 regulates self-renewal and occupies core pluripotency-related genes in embryonic stem cells. Stem Cells 27(2):317–328. doi:10.1634/stemcells.2008-0710

    Article  CAS  PubMed  Google Scholar 

  136. Singhal N, Graumann J, Wu G, Arauzo-Bravo MJ, Han DW, Greber B, Gentile L, Mann M, Scholer HR (2010) Chromatin-remodeling components of the BAF complex facilitate reprogramming. Cell 141(6):943–955. doi:10.1016/j.cell.2010.04.037

    Article  CAS  PubMed  Google Scholar 

  137. Sanchez-Tillo E, Lazaro A, Torrent R, Cuatrecasas M, Vaquero EC, Castells A, Engel P, Postigo A (2010) ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 29(24):3490–3500. doi:10.1038/onc.2010.102

    Article  CAS  PubMed  Google Scholar 

  138. Galvan JA, Helbling M, Koelzer VH, Tschan MP, Berger MD, Hadrich M, Schnuriger B, Karamitopoulou E, Dawson H, Inderbitzin D, Lugli A, Zlobec I (2015) TWIST1 and TWIST2 promoter methylation and protein expression in tumor stroma influence the epithelial–mesenchymal transition-like tumor budding phenotype in colorectal cancer. Oncotarget 6(2):874–885

    Article  PubMed  Google Scholar 

  139. Kwon MJ, Kwon JH, Nam ES, Shin HS, Lee DJ, Kim JH, Rho YS, Sung CO, Lee WJ, Cho SJ (2013) TWIST1 promoter methylation is associated with prognosis in tonsillar squamous cell carcinoma. Hum Pathol 44(9):1722–1729. doi:10.1016/j.humpath.2013.03.004

    Article  CAS  PubMed  Google Scholar 

  140. Gort EH, Suijkerbuijk KP, Roothaan SM, Raman V, Vooijs M, van der Wall E, van Diest PJ (2008) Methylation of the TWIST1 promoter, TWIST1 mRNA levels, and immunohistochemical expression of TWIST1 in breast cancer. Cancer Epidemiol Biomark Prev 17(12):3325–3330. doi:10.1158/1055-9965.EPI-08-0472

    Article  CAS  Google Scholar 

  141. Chen Y, Wang K, Qian CN, Leach R (2013) DNA methylation is associated with transcription of Snail and Slug genes. Biochem Biophys Res Commun 430(3):1083–1090. doi:10.1016/j.bbrc.2012.12.034

    Article  CAS  PubMed  Google Scholar 

  142. Acun T, Oztas E, Yagci T, Yakicier MC (2011) SIP1 is downregulated in hepatocellular carcinoma by promoter hypermethylation. BMC Cancer 11:223. doi:10.1186/1471-2407-11-223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Li A, Omura N, Hong SM, Vincent A, Walter K, Griffith M, Borges M, Goggins M (2010) Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. Cancer Res 70(13):5226–5237. doi:10.1158/0008-5472.CAN-09-4227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Liang Y, Hu J, Li J, Liu Y, Yu J, Zhuang X, Mu L, Kong X, Hong D, Yang Q, Hu G (2015) Epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Cancer Res 75(17):3672–3680. doi:10.1158/0008-5472.CAN-15-0930

    Article  CAS  PubMed  Google Scholar 

  145. Meng F, Sun G, Zhong M, Yu Y, Brewer MA (2013) Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2′-deoxycytidine on ovarian cancer. Br J Cancer 108(3):579–586. doi:10.1038/bjc.2013.10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ding W, Dang H, You H, Steinway S, Takahashi Y, Wang HG, Liao J, Stiles B, Albert R, Rountree CB (2012) miR-200b restoration and DNA methyltransferase inhibitor block lung metastasis of mesenchymal-phenotype hepatocellular carcinoma. Oncogenesis 1:e15. doi:10.1038/oncsis.2012.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Si W, Huang W, Zheng Y, Yang Y, Liu X, Shan L, Zhou X, Wang Y, Su D, Gao J, Yan R, Han X, Li W, He L, Shi L, Xuan C, Liang J, Sun L, Wang Y, Shang Y (2015) Dysfunction of the reciprocal feedback loop between GATA3- and ZEB2-nucleated repression programs contributes to breast cancer metastasis. Cancer Cell 27(6):822–836. doi:10.1016/j.ccell.2015.04.011

    Article  CAS  PubMed  Google Scholar 

  148. Zhang H, Cai K, Wang J, Wang X, Cheng K, Shi F, Jiang L, Zhang Y, Dou J (2014) MiR-7, inhibited indirectly by lincRNA HOTAIR, directly inhibits SETDB1 and reverses the EMT of breast cancer stem cells by downregulating the STAT3 pathway. Stem Cells 32(11):2858–2868. doi:10.1002/stem.1795

    Article  CAS  PubMed  Google Scholar 

  149. Oktyabri D, Tange S, Terashima M, Ishimura A, Suzuki T (2014) EED regulates epithelial–mesenchymal transition of cancer cells induced by TGF-beta. Biochem Biophys Res Commun 453(1):124–130. doi:10.1016/j.bbrc.2014.09.082

    Article  CAS  PubMed  Google Scholar 

  150. Avila-Moreno F, Armas-Lopez L, Alvarez-Moran AM, Lopez-Bujanda Z, Ortiz-Quintero B, Hidalgo-Miranda A, Urrea-Ramirez F, Rivera-Rosales RM, Vazquez-Manriquez E, Pena-Mirabal E, Morales-Gomez J, Vazquez-Minero JC, Tellez-Becerra JL, Ramirez-Mendoza R, Avalos-Bracho A, de Alba EG, Vazquez-Santillan K, Maldonado-Lagunas V, Santillan-Doherty P, Pina-Sanchez P, Zuniga-Ramos J (2014) Overexpression of MEOX2 and TWIST1 is associated with H3K27me3 levels and determines lung cancer chemoresistance and prognosis. PLoS One 9(12):e114104. doi:10.1371/journal.pone.0114104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Ezponda T, Popovic R, Shah MY, Martinez-Garcia E, Zheng Y, Min DJ, Will C, Neri A, Kelleher NL, Yu J, Licht JD (2013) The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial–mesenchymal transition and invasive properties of prostate cancer. Oncogene 32(23):2882–2890. doi:10.1038/onc.2012.297

    Article  CAS  PubMed  Google Scholar 

  152. Enkhbaatar Z, Terashima M, Oktyabri D, Tange S, Ishimura A, Yano S, Suzuki T (2013) KDM5B histone demethylase controls epithelial–mesenchymal transition of cancer cells by regulating the expression of the microRNA-200 family. Cell Cycle 12(13):2100–2112. doi:10.4161/cc.25142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Di Micco R, Fontanals-Cirera B, Low V, Ntziachristos P, Yuen SK, Lovell CD, Dolgalev I, Yonekubo Y, Zhang G, Rusinova E, Gerona-Navarro G, Canamero M, Ohlmeyer M, Aifantis I, Zhou MM, Tsirigos A, Hernando E (2014) Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9(1):234–247. doi:10.1016/j.celrep.2014.08.055

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Zhang P, Dong Z, Cai J, Zhang C, Shen Z, Ke A, Gao D, Fan J, Shi G (2015) BRD4 promotes tumor growth and epithelial–mesenchymal transition in hepatocellular carcinoma. Int J Immunopathol Pharmacol 28(1):36–44. doi:10.1177/0394632015572070

    Article  CAS  PubMed  Google Scholar 

  155. Jordan NV, Prat A, Abell AN, Zawistowski JS, Sciaky N, Karginova OA, Zhou B, Golitz BT, Perou CM, Johnson GL (2013) SWI/SNF chromatin-remodeling factor Smarcd3/Baf60c controls epithelial–mesenchymal transition by inducing Wnt5a signaling. Mol Cell Biol 33(15):3011–3025. doi:10.1128/MCB.01443-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Abba ML, Patil N, Leupold JH, Allgayer H (2016) MicroRNA regulation of epithelial to mesenchymal transition. J Clin Med. doi:10.3390/jcm5010008

    PubMed  PubMed Central  Google Scholar 

  157. Zaravinos A (2015) The regulatory role of MicroRNAs in EMT and cancer. J Oncol 2015:865816. doi:10.1155/2015/865816

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Garg M (2015) Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer. Expert Opin Ther Targets 19(2):285–297. doi:10.1517/14728222.2014.975794

    Article  CAS  PubMed  Google Scholar 

  159. Li LZ, Zhang CZ, Liu LL, Yi C, Lu SX, Zhou X, Zhang ZJ, Peng YH, Yang YZ, Yun JP (2014) miR-720 inhibits tumor invasion and migration in breast cancer by targeting TWIST1. Carcinogenesis 35(2):469–478. doi:10.1093/carcin/bgt330

    Article  PubMed  CAS  Google Scholar 

  160. Dong P, Kaneuchi M, Watari H, Sudo S, Sakuragi N (2014) MicroRNA-106b modulates epithelial–mesenchymal transition by targeting TWIST1 in invasive endometrial cancer cell lines. Mol Carcinog 53(5):349–359. doi:10.1002/mc.21983

    Article  CAS  PubMed  Google Scholar 

  161. Zuo QF, Cao LY, Yu T, Gong L, Wang LN, Zhao YL, Xiao B, Zou QM (2015) MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail. Cell Death Dis 6:e2000. doi:10.1038/cddis.2015.297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Korpal M, Lee ES, Hu G, Kang Y (2008) The miR-200 family inhibits epithelial–mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem 283(22):14910–14914. doi:10.1074/jbc.C800074200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601. doi:10.1038/ncb1722

    Article  CAS  PubMed  Google Scholar 

  164. Park SM, Gaur AB, Lengyel E, Peter ME (2008) The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev 22(7):894–907. doi:10.1101/gad.1640608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, Diehn M, Liu H, Panula SP, Chiao E, Dirbas FM, Somlo G, Pera RA, Lao K, Clarke MF (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138(3):592–603. doi:10.1016/j.cell.2009.07.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Martinez-Fernandez M, Duenas M, Feber A, Segovia C, Garcia-Escudero R, Rubio C, Lopez-Calderon FF, Diaz-Garcia C, Villacampa F, Duarte J, Gomez-Rodriguez MJ, Castellano D, Rodriguez-Peralto JL, de la Rosa F, Beck S, Paramio JM (2015) A Polycomb-mir200 loop regulates clinical outcome in bladder cancer. Oncotarget 6(39):42258–42275. doi:10.18632/oncotarget.5546

    PubMed  PubMed Central  Google Scholar 

  167. Lee JY, Kong G (2015) MEL-18, a tumor suppressor for aggressive breast cancer. Oncotarget 6(18):15710–15711. doi:10.18632/oncotarget.4565

    Article  PubMed  PubMed Central  Google Scholar 

  168. Lee JY, Park MK, Park JH, Lee HJ, Shin DH, Kang Y, Lee CH, Kong G (2014) Loss of the polycomb protein Mel-18 enhances the epithelial–mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancer. Oncogene 33(10):1325–1335. doi:10.1038/onc.2013.53

    Article  CAS  PubMed  Google Scholar 

  169. Wels C, Joshi S, Koefinger P, Bergler H, Schaider H (2011) Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial–mesenchymal transition-like phenotype in melanoma. J Invest Dermatol 131(9):1877–1885. doi:10.1038/jid.2011.142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Peiro S, Escriva M, Puig I, Barbera MJ, Dave N, Herranz N, Larriba MJ, Takkunen M, Franci C, Munoz A, Virtanen I, Baulida J, Garcia de Herreros A (2006) Snail1 transcriptional repressor binds to its own promoter and controls its expression. Nucleic Acids Res 34(7):2077–2084. doi:10.1093/nar/gkl141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Guccione E, Martinato F, Finocchiaro G, Luzi L, Tizzoni L, Dall’ Olio V, Zardo G, Nervi C, Bernard L, Amati B (2006) Myc-binding-site recognition in the human genome is determined by chromatin context. Nat Cell Biol 8(7):764–770. doi:10.1038/ncb1434

    Article  CAS  PubMed  Google Scholar 

  172. Kenneth NS, Ramsbottom BA, Gomez-Roman N, Marshall L, Cole PA, White RJ (2007) TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription. Proc Natl Acad Sci USA 104(38):14917–14922. doi:10.1073/pnas.0702909104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Bedford DC, Kasper LH, Fukuyama T, Brindle PK (2010) Target gene context influences the transcriptional requirement for the KAT3 family of CBP and p300 histone acetyltransferases. Epigenetics 5(1):9–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Vervoorts J, Luscher-Firzlaff JM, Rottmann S, Lilischkis R, Walsemann G, Dohmann K, Austen M, Luscher B (2003) Stimulation of c-MYC transcriptional activity and acetylation by recruitment of the cofactor CBP. EMBO Rep 4(5):484–490. doi:10.1038/sj.embor.embor821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Brenner C, Deplus R, Didelot C, Loriot A, Vire E, De Smet C, Gutierrez A, Danovi D, Bernard D, Boon T, Pelicci PG, Amati B, Kouzarides T, de Launoit Y, Di Croce L, Fuks F (2005) Myc represses transcription through recruitment of DNA methyltransferase corepressor. EMBO J 24(2):336–346. doi:10.1038/sj.emboj.7600509

    Article  CAS  PubMed  Google Scholar 

  176. Kurland JF, Tansey WP (2008) Myc-mediated transcriptional repression by recruitment of histone deacetylase. Cancer Res 68(10):3624–3629. doi:10.1158/0008-5472.CAN-07-6552

    Article  CAS  PubMed  Google Scholar 

  177. Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E (2007) Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol 27(5):1889–1903. doi:10.1128/MCB.01506-06

    Article  CAS  PubMed  Google Scholar 

  178. Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R (2007) Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318(5849):447–450. doi:10.1126/science.1149042

    Article  CAS  PubMed  Google Scholar 

  179. Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K (2007) PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem 282(28):20395–20406. doi:10.1074/jbc.M701574200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Tie F, Banerjee R, Conrad PA, Scacheri PC, Harte PJ (2012) Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27. Mol Cell Biol 32(12):2323–2334. doi:10.1128/MCB.06392-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Miller SA, Mohn SE, Weinmann AS (2010) Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell 40(4):594–605. doi:10.1016/j.molcel.2010.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Korkaya H, Wicha MS (2007) Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs 21(5):299–310

    Article  CAS  PubMed  Google Scholar 

  183. Zahnow CA, Topper M, Stone M, Murray-Stewart T, Li H, Baylin SB, Casero RA Jr (2016) Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy. Adv Cancer Res 130:55–111. doi:10.1016/bs.acr.2016.01.007

  184. Campbell RM, Tummino PJ (2014) Cancer epigenetics drug discovery and development: the challenge of hitting the mark. J Clin Investig 124(1):64–69. doi:10.1172/JCI71605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kim TK, Gore SD, Zeidan AM (2015) Epigenetic therapy in acute myeloid leukemia: current and future directions. Semin Hematol 52(3):172–183. doi:10.1053/j.seminhematol.2015.04.003

  186. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8(11):890–896. doi:10.1038/nchembio.1084

    CAS  PubMed  Google Scholar 

  187. Chen CW, Armstrong SA (2015) Targeting DOT1L and HOX gene expression in MLL rearranged leukemia and beyond. Exp Hematol 43(8):673–684. doi:10.1016/j.exphem.2015.05.012

  188. Pereira F, Barbachano A, Silva J, Bonilla F, Campbell MJ, Munoz A, Larriba MJ (2011) KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet 20(23):4655–4665. doi:10.1093/hmg/ddr399

    Article  CAS  PubMed  Google Scholar 

  189. Wang CY, Filippakopoulos P (2015) Beating the odds: BETs in disease. Trends Biochem Sci 40(8):468–479. doi:10.1016/j.tibs.2015.06.002

    Article  CAS  PubMed  Google Scholar 

  190. Meng F, Sun G, Zhong M, Yu Y, Brewer MA (2013) Inhibition of DNA methyltransferases, histone deacetylases and lysine-specific demethylase-1 suppresses the tumorigenicity of the ovarian cancer ascites cell line SKOV3. Int J Oncol 43(2):495–502. doi:10.3892/ijo.2013.1960

    CAS  PubMed  Google Scholar 

  191. Javaid S, Zhang J, Anderssen E, Black JC, Wittner BS, Tajima K, Ting DT, Smolen GA, Zubrowski M, Desai R, Maheswaran S, Ramaswamy S, Whetstine JR, Haber DA (2013) Dynamic chromatin modification sustains epithelial–mesenchymal transition following inducible expression of Snail-1. Cell reports 5(6):1679–1689. doi:10.1016/j.celrep.2013.11.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Lee JY, Kong G (2015) DOT1L: a new therapeutic target for aggressive breast cancer. Oncotarget 6(31):30451–30452. doi:10.18632/oncotarget.5860

    PubMed  PubMed Central  Google Scholar 

  193. Zhang L, Deng L, Chen F, Yao Y, Wu B, Wei L, Mo Q, Song Y (2014) Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer. Oncotarget 5(21):10665–10677. doi:10.18632/oncotarget.2496

    Article  PubMed  PubMed Central  Google Scholar 

  194. Yoshikawa M, Hishikawa K, Marumo T, Fujita T (2007) Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. J Am Soc Nephrol 18(1):58–65. doi:10.1681/ASN.2005111187

    Article  CAS  PubMed  Google Scholar 

  195. Xie L, Santhoshkumar P, Reneker LW, Sharma KK (2014) Histone deacetylase inhibitors trichostatin A and vorinostat inhibit TGFbeta2-induced lens epithelial-to-mesenchymal cell transition. Invest Ophthalmol Vis Sci 55(8):4731–4740. doi:10.1167/iovs.14-14109

    Article  CAS  PubMed  Google Scholar 

  196. Ruscetti M, Dadashian EL, Guo W, Quach B, Mulholland DJ, Park JW, Tran LM, Kobayashi N, Bianchi-Frias D, Xing Y, Nelson PS, Wu H (2015) HDAC inhibition impedes epithelial–mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene. doi:10.1038/onc.2015.444

    PubMed  PubMed Central  Google Scholar 

  197. Sakamoto T, Kobayashi S, Yamada D, Nagano H, Tomokuni A, Tomimaru Y, Noda T, Gotoh K, Asaoka T, Wada H, Kawamoto K, Marubashi S, Eguchi H, Doki Y, Mori M (2016) A histone deacetylase inhibitor suppresses epithelial–mesenchymal transition and attenuates chemoresistance in biliary tract cancer. PLoS One 11(1):e0145985. doi:10.1371/journal.pone.0145985

    Article  PubMed  PubMed Central  Google Scholar 

  198. Schech A, Kazi A, Yu S, Shah P, Sabnis G (2015) Histone deacetylase inhibitor entinostat inhibits tumor-initiating cells in triple-negative breast cancer cells. Mol Cancer Ther 14(8):1848–1857. doi:10.1158/1535-7163.MCT-14-0778

    Article  CAS  PubMed  Google Scholar 

  199. Kong D, Ahmad A, Bao B, Li Y, Banerjee S, Sarkar FH (2012) Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. PLoS One 7(9):e45045. doi:10.1371/journal.pone.0045045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Ji M, Lee EJ, Kim KB, Kim Y, Sung R, Lee SJ, Kim DS, Park SM (2015) HDAC inhibitors induce epithelial–mesenchymal transition in colon carcinoma cells. Oncol Rep 33(5):2299–2308. doi:10.3892/or.2015.3879

    PubMed  Google Scholar 

  201. Wu S, Luo Z, Yu PJ, Xie H, He YW (2016) Suberoylanilide hydroxamic acid (SAHA) promotes the epithelial mesenchymal transition of triple negative breast cancer cells via HDAC8/FOXA1 signals. Biol Chem 397(1):75–83. doi:10.1515/hsz-2015-0215

    Article  CAS  PubMed  Google Scholar 

  202. Jiang GM, Wang HS, Zhang F, Zhang KS, Liu ZC, Fang R, Wang H, Cai SH, Du J (2013) Histone deacetylase inhibitor induction of epithelial–mesenchymal transitions via up-regulation of Snail facilitates cancer progression. Biochim Biophys Acta 1833(3):663–671. doi:10.1016/j.bbamcr.2012.12.002

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean government (No. 2015R1A2A1A10052578).

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  1. Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Republic of Korea

    Jeong-Yeon Lee

  2. Department of Pathology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea

    Gu Kong

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Lee, JY., Kong, G. Roles and epigenetic regulation of epithelial–mesenchymal transition and its transcription factors in cancer initiation and progression. Cell. Mol. Life Sci. 73, 4643–4660 (2016). https://doi.org/10.1007/s00018-016-2313-z

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  • DOI: https://doi.org/10.1007/s00018-016-2313-z

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