A comprehensive review of lysine-specific demethylase 1 and its roles in cancer

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8(9), 724–732 (2009).
  Medline CASGoogle Scholar
• 2 Bedford MT, Richard S. Arginine methylation: an emerging regulator of protein function. Mol. Cell 18, 263–272 (2005).
  Medline CASGoogle Scholar
• 3 Jones PA, Martienssen R. A blueprint for a Human Epigenome Project: the AACR Human Epigenome Workshop. Cancer Res. 65, 11241–11246 (2005).
  Medline CASGoogle Scholar
• 4 Martin C, Zhang Y. The diverse functions of histone lysine methylation. Nat. Rev. Mol. Cell Biol. 6, 838–849 (2005).
  Medline CASGoogle Scholar
• 5 Kouzarides T. Chromatin modifi cations and their function. Cell 128(4), 693–705 (2007).
  Medline CASGoogle Scholar
• 6 Morera L, Lubbert M, Jung M. Targeting histone methyltanserases and demethylases in clinical trial for cancer therapy. Clin. Epigenetics 8, 57 (2016).
  MedlineGoogle Scholar
• 7 Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).
  Medline CASGoogle Scholar
• 8 Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat. Rev. Cancer 7(11), 823–833 (2007).
  Medline CASGoogle Scholar
• 9 Hu D, Shilatifard A. Epigenetics of hematopoiesis and hematological malignancies. Genes Dev. 30(18), 2021–2041 (2016).
  Medline CASGoogle Scholar
• 10 Adachi Y, Takeuchi T, Nagayama T, Furihata M. T-cadherin modulates tumor-associated molecules in gallbladder cancer cells. Cancer Invest. 28(2), 120–126 (2010).
  Medline CASGoogle Scholar
• 11 Nakakido M, Deng Z, Suzuki T, Dohmae N, Nakamura Y, Hamamoto R. Dysregulation of AKT pathway by SMYD2-mediated lysine methylation on PTEN. Neoplasia 17(4), 367–373 (2015).
  Medline CASGoogle Scholar
• 12 Komatsu S, Imoto I, Tsuda H et al. Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30(7), 1139–1146 (2009).
  Medline CASGoogle Scholar
• 13 Pires-Luís AS, Vieira-Coimbra M, Vieira FQ et al. Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication. Epigenetics 10(11), 1033–1043 (2015).
  MedlineGoogle Scholar
• 14 Sakamoto LH, Andrade RV, Felipe MS, Motoyama AB, Pittella Silva F. SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. Leuk. Res. 38(4), 496–502 (2014).
  Medline CASGoogle Scholar
• 15 Hamamoto R, Furukawa Y, Morita M et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat. Cell Biol. 6(8), 731–740 (2004).
  Medline CASGoogle Scholar
• 16 Demelash A, Rudrabhatla P, Pant HC et al. Achaete-scute homologue-1 (ASH1) stimulates migration of lung cancer cells through Cdk5/p35 pathway. Mol. Biol. Cell 23(15), 2856–2866 (2012).
  Medline CASGoogle Scholar
• 17 Rapa I, Ceppi P, Bollito E et al. Human ASH1 expression in prostate cancer with neuroendocrine differentiation. Mod. Pathol. 21(6), 700–707 (2008).
  Medline CASGoogle Scholar
• 18 Dong C, Wu Y, Wang Y et al. Interaction with Suv39H1 is critical for Snail-mediated E-cadherin repression in breast cancer. Oncogene 32(11), 1351–1362 (2013).
  Medline CASGoogle Scholar
• 19 Lai YS, Chen JY, Tsai HJ, Chen TY, Hung WC. The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells. Blood Cancer J. 5, e313 (2015).
  MedlineGoogle Scholar
• 20 Spyropoulou A, Gargalionis A, Dalagiorgou G et al. Role of histone lysine methyltransferases SUV39H1 and SETDB1 in gliomagenesis: modulation of cell proliferation, migration, and colony formation. Neuromolecular Med. 16(1), 70–82 (2014).
  Medline CASGoogle Scholar
• 21 Spyropoulou A, Gargalionis A, Dalagiorgou G et al. Histone lysine methyltransferase SUV39H1 is a potent target for epigenetic therapy of hepatocellular carcinoma. Int. J. Cancer 136(2), 289–298 (2015).
  MedlineGoogle Scholar
• 22 Piao L, Suzuki T, Dohmae N, Nakamura Y, Hamamoto R. SUV39H2 methylates and stabilizes LSD1 by inhibiting polyubiquitination in human cancer cells. Oncotarget 6(19), 16939–16950 (2015).
  MedlineGoogle Scholar
• 23 Yoon KA, Hwangbo B, Kim IJ et al. Novel polymorphisms in the SUV39H2 histone methyltransferase and the risk of lung cancer. Carcinogenesis 27(11), 2217–2222 (2006).
  Medline CASGoogle Scholar
• 24 Hung SY, Lin HH, Yeh KT, Chang JG. Histone-modifying genes as biomarkers in hepatocellular carcinoma. Int. J. Clin. Exp. Pathol. 7(5), 2496–2507 (2014).
  Medline CASGoogle Scholar
• 25 Kim KB, Son HJ, Choi S et al. H3K9 methyltransferase G9a negatively regulates UHRF1 transcription during leukemia cell differentiation. Nucleic Acids Res. 43(7), 3509–3523 (2015).
  Medline CASGoogle Scholar
• 26 Casciello F, Windloch K, Gannon F, Lee JS. Functional role of G9a histone methyltransferase in cancer. Front. Immunol. 6, 487 (2015).
  MedlineGoogle Scholar
• 27 Li KC, Hua KT, Lin YS et al. Inhibition of G9a induces DUSP4 dependent autophagic cell death in head and neck squamous cellcarcinoma. Mol. Cancer 13, 172 (2014).
  MedlineGoogle Scholar
• 28 Tao H, Li H, Su Y et al. Histone methyltransferase G9a and H3K9 dimethylation inhibit the self-renewal of glioma cancer stem cells. Mol. Cell Biochem. 394(1–2), 23–30 (2014).
  Medline CASGoogle Scholar
• 29 Pappano WN, Guo J, He Y et al. The histone methyltransferase inhibitor A-366 uncovers a role for G9a/GLP in the epigenetics of leukemia. PLoS ONE 10(7), e0131716 (2015).
  MedlineGoogle Scholar
• 30 Sun Y, Wei M, Ren SC et al. Histone methyltransferase SETDB1 is required for prostate cancer cell proliferation, migration and invasion. Asian J. Androl. 16(2), 319–324 (2014).
  MedlineGoogle Scholar
• 31 Rodriguez-Paredes M, Martinez de Paz A, Simó-Riudalbas L et al. Gene amplification of the histone methyltransferase SETDB1 contributes to human lung tumorigenesis. Oncogene 33(21), 2807–2813 (2014).
  Medline CASGoogle Scholar
• 32 Du Y, Carling T, Fang W, Piao Z, Sheu JC, Huang S. Hypermethylation in human cancers of the RIZ1 tumor suppressor gene, a member of a histone/protein methyltransferase superfamily. Cancer Res. 61(22), 8094–8099 (2001).
  Medline CASGoogle Scholar
• 33 Margueron R, Li G, Sarma K et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32(4), 503–518 (2008).
  Medline CASGoogle Scholar
• 34 Mochizuki-Kashio M, Aoyama K, Sashida G et al. Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. Blood 126(10), 1172–1183 (2015).
  Medline CASGoogle Scholar
• 35 Lund K, Adams PD, Copland M. EZH2 in normal and malignant hematopoiesis. Leukemia 28(1), 44–49 (2014).
  Medline CASGoogle Scholar
• 36 Fussbroich B, Wagener N, Macher-Goeppinger S et al. EZH2 depletion blocks the proliferation of colon cancer cells. PLoS ONE 6(7), e21651 (2011).
  Medline CASGoogle Scholar
• 37 Yang YA, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein Cell 4(5), 331–341 (2013).
  Medline CASGoogle Scholar
• 38 Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat. Med. 22(2), 128–134 (2016).
  Medline CASGoogle Scholar
• 39 Kleer CG, Cao Q, Varambally S et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl. Acad. Sci. USA 100(20), 11606–11611 (2003).
  Medline CASGoogle Scholar
• 40 Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST et al. NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. Blood 118(13), 3645–3656 (2011).
  Medline CASGoogle Scholar
• 41 Lucio-Eterovic AK, Carpenter PB. An open and shut case for the role of NSD proteins as oncogenes. Transcription 2(4), 158–161 (2011).
  MedlineGoogle Scholar
• 42 Jaffe JD, Wang Y, Chan HM et al. Global chromatin profiling reveals NSD2 mutations in pediatric acute lymphoblastic leukemia. Nat. Genet. 45(11), 1386–1391 (2013).
  Medline CASGoogle Scholar
• 43 Yang P, Guo L, Duan ZJ et al. Histone methyltransferase NSD2/MMSET mediates constitutive NF-κB signaling for cancer cell proliferation, survival, and tumor growth via a feed-forward loop. Mol. Cell Biol. 32(15), 3121–3131 (2012).
  Medline CASGoogle Scholar
• 44 Rosati R, La Starza R, Veronese A et al. NUP98 is fused to the NSD3 gene in acute myeloid leukemia associated with t (8;11) (p11.2; p15). Blood 99(10), 3857–3860 (2002).
  Medline CASGoogle Scholar
• 45 McLean CM, Karemaker ID, van Leeuwen F. The emerging roles of DOT1L in leukemia and normal development. Leukemia 28(11), 2131–2138 (2014).
  Medline CASGoogle Scholar
• 46 Annala M, Kivinummi K, Leinonen K et al. DOT1L-HES6 fusion drives androgen independent growth in prostate cancer. EMBO Mol. Med. 6(9), 1121–1123 (2014).
  Medline CASGoogle Scholar
• 47 Lee JY, Kong G. DOT1L: a new therapeutic target for aggressive breast cancer. Oncotarget 6(31), 30451–30452 (2015).
  MedlineGoogle Scholar
• 48 Liu B, Zhang X, Song F et al. A functional single nucleotide polymorphism of SET8 is prognostic for breast cancer. Oncotarget 7(23), 34277–34287 (2016).
  MedlineGoogle Scholar
• 49 Evertts AG, Manning AL, Wang X, Dyson NJ, Garcia BA, Coller HA. H4K20 methylation regulates quiescence and chromatin compaction. Mol. Biol. Cell 24(19), 3025–3037 (2013).
  Medline CASGoogle Scholar
• 50 Shi Y, Lan F, Matson C et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD. Cell 119, 941–953 (2004). •• Identifies LSD1 as a histone demethylase.
  Medline CASGoogle Scholar
• 51 Morera L, Lubbert M, Jung M. Targeting histone methyltanserases and demethylases in clinical trial for cancer therapy. Clin. Epigenetics 8, 57 (2016).
  MedlineGoogle Scholar
• 52 Højfeldt JW, Agger K, Helin K. Histone lysine demethylases as targets for anticancer therapy. Nat. Rev. Drug Discov. 12(12), 917–930 (2013).
  Medline CASGoogle Scholar
• 53 Wissmann M, Yin N, Müller JM et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat. Cell Biol. 9(3), 347–353 (2007).
  Medline CASGoogle Scholar
• 54 Lim S, Janzer A, Becker A et al. Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology. Carcinogenesis 31(3), 512–520 (2010).
  Medline CASGoogle Scholar
• 55 Huang Y, Vasilatos SN, Boric L, Shaw PG, Davidson NE. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res. Treat. 131(3), 777–789 (2012).
  Medline CASGoogle Scholar
• 56 Chen C, Zhao M, Yin N et al. Abnormal histone acetylation and methylation levels in esophageal squamous cell carcinomas. Cancer Investig. 29(8), 548–556 (2011).
  Medline CASGoogle Scholar
• 57 Ding J, Zhang ZM, Xia Y et al. LSD1-mediated epigenetic modification contributes to proliferation and metastasis of colon cancer. Br. J. Cancer 109(4), 994–1003 (2013).
  Medline CASGoogle Scholar
• 58 Jin L, Hanigan CL, Wu Y et al. Loss of LSD1 (lysine-specific demethylase 1) suppresses growth and alters gene expression of human colon cancer cells in a p53- and DNMT1(DNA methyltransferase 1)-independent manner. Biochem. J. 449(2), 459–568 (2013).
  Medline CASGoogle Scholar
• 59 Rao M, Chinnasamy N, Hong JA et al. Inhibition of histone lysine methylation enhances cancer-testis antigen expression in lung cancer cells: Implications for adoptive immunotherapy of cancer. Cancer Res. 71(12), 4192–4204 (2011).
  Medline CASGoogle Scholar
• 60 Bennani-Baiti IM, Machado I, Llombart-Bosch A, Kovar H. Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Hum. Pathol. 43(8), 1300–1307 (2012).
  Medline CASGoogle Scholar
• 61 Kahl P, Gullotti L, Heukamp LC et al. Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res. 66(23), 11341–11347 (2006).
  Medline CASGoogle Scholar
• 62 Hayami S, Kelly JD, Cho HS et al. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int. J. Cancer 128(3), 574–586 (2011).
  Medline CASGoogle Scholar
• 63 Kauffman EC, Robinson BD, Downes MJ et al. Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol. Carcinog. 50(12), 931–944 (2011).
  Medline CASGoogle Scholar
• 64 Schulte JH, Lim S, Schramm A et al. Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. Cancer Res. 69, 2065–2071 (2009).
  Medline CASGoogle Scholar
• 65 Lv T, Yuan D, Miao X et al. Over-expression of LSD1 promotes proliferation, migration and invasion in non-small-cell lung cancer. PLoS ONE 7, e35065 (2012).
  Medline CASGoogle Scholar
• 66 Feng J, Li L, Zhang N et al. Androgen and AR contribute to breast cancer development and metastasis: an insight of mechanisms. Oncogene 1–16 (2016).
  Google Scholar
• 67 Rhodes DR, Kalyana-Sundaram S, Mahavisno V et al. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 9, 166–180 (2007).
  Medline CASGoogle Scholar
• 68 Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 113, 3088–3091 (2009).
  Medline CASGoogle Scholar
• 69 Goardon N, Marchi E, Atzberger A et al. Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell 19, 138–152 (2011).
  Medline CASGoogle Scholar
• 70 Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10, 257–268 (2006).
  Medline CASGoogle Scholar
• 71 Somervaille TC, Matheny CJ, Spencer GJ et al. Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 4, 129–140 (2009).
  Medline CASGoogle Scholar
• 72 Harris WJ, Huang X, Lynch JT et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012). •• Provides evidence for a critical role of LSD1 in acute myeloid leukemia (AML) and explore the preclinical evidence for activity of a specific LSD1 inhibitor in an animal model of MLL-AF9 leukemia.
  Medline CASGoogle Scholar
• 73 Zhao ZK, Dong P, Gu J et al. Overexpression of LSD1 in hepatocellular carcinoma: a latent target for the diagnosis and therapy of hepatoma. Tumour Biol. 34(1), 173–180 (2013).
  MedlineGoogle Scholar
• 74 Heidenblad M, Lindgren D, Jonson T et al. Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. BMC Med. Genom. 1, 3 (2008).
  MedlineGoogle Scholar
• 75 Vogt T, Kroiss M, McClelland M et al. Deficiency of a novel retinoblastoma binding protein 2-homolog is a consistent feature of sporadic human melanoma skin cancer. Lab. Invest. 79, 1615–1627 (1999).
  Medline CASGoogle Scholar
• 76 van Zutven LJ, Onen E, Velthuizen SC et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 45, 437–446 (2006).
  Medline CASGoogle Scholar
• 77 Hayami S, Yoshimatsu M, Veerakumarasivam A et al. Overexpression of the JmjC histone demethylase KDM5B in human carcinogenesis: involvement in the proliferation of cancer cells through the E2F/RB pathway. Mol. Cancer 9, 59 (2010).
  MedlineGoogle Scholar
• 78 Xiang Y, Zhu Z, Han G et al. JARID1B is a histone H3 lysine 4 demethylase upregulated in prostate cancer. Proc. Natl Acad. Sci. USA 104, 19226–19231 (2007).
  Medline CASGoogle Scholar
• 79 Lu PJ, Sundquist K, Baeckstrom D et al. A novel gene (PLU-1) containing highly conserved putative DNA/chromatin binding motifs is specifically up-regulated in breast cancer. J. Biol. Chem. 274, 15633–15645 (1999).
  Medline CASGoogle Scholar
• 80 Barrett A, Madsen B, Copier J et al. PLU-1 nuclear protein, which is upregulated in breast cancer, shows restricted expression in normal human adult tissues: a new cancer/testis antigen? Int. J. Cancer 101, 581–588 (2002).
  Medline CASGoogle Scholar
• 81 Dalgliesh GL, Furge K, Greenman C et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463(7279), 360–363 (2010).
  Medline CASGoogle Scholar
• 82 Stein J, Majores M, Rohde M et al. KDM5C is overexpressed in prostate cancer and is a prognostic marker for prostate-specific antigen-relapse following radical prostatectomy. Am. J. Pathol. 184(9), 2430–7 (2014).
  Medline CASGoogle Scholar
• 83 Perinchery G, Sasaki M, Angan A, Kumar V, Carroll P, Dahiya R. Deletion of Y-chromosome specific genes in human prostate cancer. J. Urol. 163, 1339–1342 (2000).
  Medline CASGoogle Scholar
• 84 Suzuki C, Takahashi K, Hayama S et al. Identification of Myc-associated protein with JmjC domain as a novel therapeutic target oncogene for lung cancer. Mol. Cancer Ther. 6, 542–551 (2007).
  Medline CASGoogle Scholar
• 85 Uemura M1, Yamamoto H, Takemasa I et al. Jumonji domain containing 1A is a novel prognostic marker for colorectal cancer: in vivo identification from hypoxic tumor cells. Clin. Cancer Res. 6, 4636–4646 (2010).
  Google Scholar
• 86 Qi J, Nakayama K, Cardiff RD et al. Siah2-dependent concerted activity of HIF and FoxA2 regulates formation of neuroendocrine phenotype and neuroendocrine prostate tumors. Cancer Cell 18, 23–38 (2010).
  Medline CASGoogle Scholar
• 87 Guo X, Shi M, Sun L et al. The expression of histone demethylase JMJD1A in renal cell carcinoma. Neoplasma 58, 153–157 (2011).
  Medline CASGoogle Scholar
• 88 Yamada D, Kobayashi S, Yamamoto H et al. Role of the hypoxia-related gene, JMJD1A, in hepatocellular carcinoma: clinical impact on recurrence after hepatic resection. Ann. Surg. Oncol. 19, 355–364 (2011).
  Google Scholar
• 89 Kim TK, Gore SD, Zeidan AM. Epigenetic therapy in acute myeloid leukemia: current and future directions. Semin. Hematol. 52(3), 172–183 (2015).
  MedlineGoogle Scholar
• 90 Patani N, Jiang WG, Newbold RF, Mokbel K. Histone-modifier gene expression profiles are associated with pathological and clinical outcomes in human breast cancer. Anticancer Res. 31, 4115–4125 (2011).
  Medline CASGoogle Scholar
• 91 Pryor JG, Brown-Kipphut BA, Iqbal A, Scott GA. Microarray comparative genomic hybridization detection of copy number changes in desmoplastic melanoma and malignant peripheral nerve sheath tumor. Am. J. Dermatopathol 33, 780–785 (2011).
  MedlineGoogle Scholar
• 92 Liu G, Bollig-Fischer A, Kreike B et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28, 4491–4500 (2009).
  Medline CASGoogle Scholar
• 93 Ehrbrecht A, Müller U, Wolter M et al. Comprehensive genomic analysis of desmoplastic medulloblastomas: identification of novel amplified genes and separate evaluation of the different histological components. J. Pathol. 208, 554–563 (2006).
  Medline CASGoogle Scholar
• 94 Vinatzer U, Gollinger M, Müllauer L, Raderer M, Chott A, Streubel B. Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN. Clin. Cancer Res. 14(20), 6426–6431 (2008).
  Medline CASGoogle Scholar
• 95 Sinha S, Singh RK, Alam N, Roy A, Roychoudhury S, Panda CK. Alterations in candidate genes PHF2, FANCC, PTCH1 and XPA at chromosomal 9q22.3 region: pathological significance in early- and late onset breast carcinoma. Mol. Cancer 7, 84 (2008).
  MedlineGoogle Scholar
• 96 Ghosh A, Ghosh S, Maiti GP et al. Association of FANCC and PTCH1 with the development of early dysplastic lesions of the head and neck. Ann. Surg. Oncol. 19, 528–538 (2011).
  Google Scholar
• 97 Agger K, Cloos PA, Rudkjaer L et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 23, 1171–1176 (2009).
  Medline CASGoogle Scholar
• 98 Barradas M, Anderton E, Acosta JC et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 23, 1177–1182 (2009).
  Medline CASGoogle Scholar
• 99 van Haaften G, Dalgliesh GL, Davies H et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).
  Medline CASGoogle Scholar
• 100 Shen Y, Guo X, Wang Y et al. Expression and significance of histone H3K27 demethylases in renal cell carcinoma. BMC Cancer 12, 470 (2012).
  Medline CASGoogle Scholar
• 101 Gui Y, Guo G, Huang Y et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat. Genet. 43, 875–878 (2011).
  Medline CASGoogle Scholar
• 102 Jankowska AM, Makishima H, Tiu RV et al. Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 118, 3932–3941 (2011).
  Medline CASGoogle Scholar
• 103 Kottakis F, Polytarchou C, Foltopoulou P, Sanidas I, Kampranis SC, Tsichlis PN. FGF-2 regulates cell proliferation, migration, and angiogenesis through an NDY1/KDM2BmiR-101-EZH2 pathway. Mol. Cell 43, 285–298 (2011).
  Medline CASGoogle Scholar
• 104 He J, Nguyen AT, Zhang Y. KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood 117, 3869–3880 (2011).
  Medline CASGoogle Scholar
• 105 Tzatsos A, Paskaleva P, Ferrari F et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123(2), 727–739 (2013).
  Medline CASGoogle Scholar
• 106 Zhang X, Bolt M, Guertin MJ et al. Peptidylarginine deiminase 2-catalyzed histone H3 arginine 26 citrullination facilitates estrogen receptor alpha target gene activation. Proc. Natl Acad. Sci. USA 109, 13331–13336 (2012).
  Medline CASGoogle Scholar
• 107 Wang Y, Wysocka J, Sayegh J et al. Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279–283 (2004).
  Medline CASGoogle Scholar
• 108 Kooistra SM, Helin K. Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13, 297–311 (2012).
  Medline CASGoogle Scholar
• 109 Hausinger RP. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit. Rev. Biochem. Mol. Biol. 39, 21–68 (2004).
  Medline CASGoogle Scholar
• 110 McDonough MA. Structural studies on human 2-oxoglutarate dependent oxygenases. Curr. Opin. Struct. Biol. 20, 659–672 (2010).
  Medline CASGoogle Scholar
• 111 Whetstine JR, Nottke A, Lan F et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).
  Medline CASGoogle Scholar
• 112 Klose RJ, Yamane K, Bae Y et al. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442, 312–316 (2006).
  Medline CASGoogle Scholar
• 113 Cloos PA, Christensen J, Agger K et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).
  Medline CASGoogle Scholar
• 114 Fodor BD, Kubicek S, Yonezawa M et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).
  Medline CASGoogle Scholar
• 115 Forneris F, Binda C, Vanoni MA, Battaglioli E, Mattevi A. Human histone demethylase LSD1 reads the histone code. J. Biol. Chem. 280(50), 41360–41365 (2005).
  Medline CASGoogle Scholar
• 116 Edmondson DE, Binda C, Mattevi A. Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B. Arch. Biochem. Biophys. 464, 269–276 (2007).
  Medline CASGoogle Scholar
• 117 Chen Y, Yang Y, Wang F et al. Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc. Natl Acad. Sci. USA 103, 13956–13961 (2006). •• Characterizes crystal structure of human LSD1.
  Medline CASGoogle Scholar
• 118 Rotili D, Mai A. Targeting histone demethylases: a new avenue for the fight against cancer. Genes Cancer 2(6), 663–679 (2011).
  Medline CASGoogle Scholar
• 119 Zheng YC, Ma J, Wang Z et al. A systematic review of histone lysine-specific demethylase 1 and its inhibitors. Med. Res. Rev. 35(5), 1032–1071 (2015). • Describes the different classes of LSD1 inhibitors.
  Medline CASGoogle Scholar
• 120 Stavropoulos P, Blobel G, Hoelz A. Crystal structure and mechanism of human lysine-specific demethylase-Nat. Struct. Mol. Biol. 13, 626–632 (2006). •• Reports detailed structural study of human LSD1.
  Medline CASGoogle Scholar
• 121 Hou H, Yu H. Structural insights into histone lysine demethylation. Curr. Opin. Struct. Biol. 20(6), 739–748 (2010).
  Medline CASGoogle Scholar
• 122 Wang J, Scully K, Zhu X et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446(7138), 882–887 (2007).
  Medline CASGoogle Scholar
• 123 Biswas D, Milne TA, Basrur V et al. Function of leukemogenic mixed lineage leukemia 1 (MLL) fusion proteins through distinct partner protein complexes. Proc. Natl Acad. Sci. USA 108, 15751–15756 (2011).
  Medline CASGoogle Scholar
• 124 Nakamura T, Mori T, Tada S et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002).
  Medline CASGoogle Scholar
• 125 Zibetti C, Adamo A, Binda C et al. Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J. Neurosci. 30(7), 2521–2532 (2010).
  Medline CASGoogle Scholar
• 126 Wang J, Telese F, Tan Y et al. LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nat. Neurosci. 18(9), 1256–1264 (2015). • Demonstrates the roles of the LSD1 neurospecific variant in neuronal differentiation.
  Medline CASGoogle Scholar
• 127 Lee MG, Wynder C, Bochar DA, Hakimi MA, Cooch N, Shiekhattar R. Functional interplay between histone demethylase and deacetylase enzymes. Mol. Cell. Biol. 26, 6395–6402 (2006).
  Medline CASGoogle Scholar
• 128 Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regulation of LSD1 histone demethylase activity by its associated factors. Mol. Cell 19, 857–864 (2005). • Reports requirement of protein co-factors for nucleosomal demethylation by LSD1.
  Medline CASGoogle Scholar
• 129 Lin Y, Wu Y, Li J et al. The SNAG domain of Snail1 functions as a molecular hook for recruiting lysine-specific demethylase. EMBO J. 29(11), 1803–1816 (2010).
  Medline CASGoogle Scholar
• 130 Wang J, Hevi S, Kurash JK et al. The lysine demethylase LSD1 is required for maintenance of global DNA methylation. Nat. Genet. 41(1), 125–129 (2009).
  Medline CASGoogle Scholar
• 131 Adamo A, Sesé B, Boue S et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat. Cell Biol. 13(6), 652–659 (2011).
  Medline CASGoogle Scholar
• 132 Foster CT, Dovey OM, Lezina L et al. Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST stability. Mol. Cell Biol. 30(20), 4851–4863 (2010).
  Medline CASGoogle Scholar
• 133 Sun G, Alzayady K, Stewart R et al. Histone demethylase LSD1 regulates neural stem cell proliferation. Mol. Cell Biol. 30(8), 1997–2005 (2010).
  Medline CASGoogle Scholar
• 134 Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99(11), 7420–7425 (2002).
  Medline CASGoogle Scholar
• 135 Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell 121(4), 645–657 (2005).
  Medline CASGoogle Scholar
• 136 Sun G, Ye P, Murai K et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat. Commun. 2(529), 1–10 (2011).
  Google Scholar
• 137 Yokoyama A, Takezawa S, Schüle R, Kitagawa H, Kato S. Transrepressive function of TLX requires the histone demethylase LSD. Mol. Cell Biol. 28, 3995–4003 (2008).
  Medline CASGoogle Scholar
• 138 Kim J, Singh AK, Takata Y et al. LSD1 is essential for oocyte meiotic progression by regulating CDC25B expression in mice. Nat. Commun. 6, 10116 (2015).
  Medline CASGoogle Scholar
• 139 Musri MM, Carmona MC, Hanzu FA, Kaliman P, Gomis R, Párrizas M. Histone demethylase LSD1 regulates adipogenesis. J. Biol. Chem. 285(39), 30034–30041 (2010).
  Medline CASGoogle Scholar
• 140 Choi J, Jang H, Kim H, Kim ST, Cho EJ, Youn HD. Histone demethylase LSD1 is required to induce skeletal muscle differentiation by regulating myogenic factors. Biochem. Biophys. Res. Commun. 401(3), 327–332 (2010).
  Medline CASGoogle Scholar
• 141 Thambyrajah R, Mazan M, Patel R et al. GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD. Nat. Cell Biol. 18(1), 21–32 (2015).
  MedlineGoogle Scholar
• 142 Takeuchi M, Fuse Y, Watanabe M et al. LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv. Proc. Natl Acad. Sci. USA 112(45), 13922–13927 (2015).
  Medline CASGoogle Scholar
• 143 Kerenyi MA, Shao Z, Hsu YJ et al. Histone demethylase LSD1 represses hematopoietic stem and progenitor cell signatures during blood cell maturation. Elife 2, e00633 (2013). • Identifies the role of LSD1 in hematopoiesis.
  MedlineGoogle Scholar
• 144 Saleque S, Kim J, Rooke HM, Orkin SH. Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD. Mol. Cell 27, 562–572 (2007). • Identifies LSD1 as mediators of the regulation of hematopoiesis.
  Medline CASGoogle Scholar
• 145 Hu X, Li X, Valverde K et al. LSD1-mediated epigenetic modification is required for TAL1 function and hematopoiesis. Proc. Natl Acad. Sci. USA 106(25), 10141–10146 (2009).
  Medline CASGoogle Scholar
• 146 Su ST, Ying HY, Chiu YK, Lin FR, Chen MY, Lin KI. Involvement of histone demethylase LSD1 in Blimp-1-mediated gene repression during plasma cell differentiation. Mol. Cell Biol. 29(6), 1421–1431 (2009).
  Medline CASGoogle Scholar
• 147 Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014).
  Medline CASGoogle Scholar
• 148 Ferrari-Amorotti G, Fragliasso V, Esteki R et al. Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion. Cancer Res. 73(1), 235–245 (2013).
  Medline CASGoogle Scholar
• 149 Wang Y, Zhang H, Chen Y et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138(4), 660–672 (2009).
  Medline CASGoogle Scholar
• 150 Whyte WA, Bilodeau S, Orlando DA et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature 482(7384), 221–225 (2012).
  Medline CASGoogle Scholar
• 151 Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature 437, 432–435 (2005). • Reports the essential role of CoREST for the demethylase activity of LSD1.
  Medline CASGoogle Scholar
• 152 Li Q, Shi L, Gui B et al. Binding of the JmjC demethylase JARID1B to LSD1/NuRD suppresses angiogenesis and metastasis in breast cancer cells by repressing chemokine CCL14. Cancer Res. 71(21), 6899–6908 (2011).
  Medline CASGoogle Scholar
• 153 Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).
  Medline CASGoogle Scholar
• 154 Sakamoto A, Hino S, Nagaoka K et al. Lysine demethylase LSD1 coordinates glycolytic and mitochondrial metabolism in hepatocellular carcinoma cells. Cancer Res. 75, 1445–1456 (2015).
  Medline CASGoogle Scholar
• 155 Qin Y, Zhu W, Xu W et al. LSD1 sustains pancreatic cancer growth via maintaining HIF1alpha-dependent glycolytic process. Cancer Lett. 347, 225–232 (2014).
  Medline CASGoogle Scholar
• 156 Hino S, Sakamoto A, Nagaoka K et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat. Commun. 3, 758 (2012).
  MedlineGoogle Scholar
• 157 Garcia-Bassets I, Kwon YS, Telese F et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128, 505–518 (2007).
  Medline CASGoogle Scholar
• 158 Metzger E, Wissmann M, Yin N et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005). • Reports ability of LSD1 to demethylate H3K9.
  Medline CASGoogle Scholar
• 159 Yang M, Gocke CB, Luo X et al. Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase. Mol. Cell 23, 377–387 (2006).
  Medline CASGoogle Scholar
• 160 Nair SS, Nair BC, Cortez V et al. PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor-alpha target gene activation by regulating lysine demethylase 1 specificity. EMBO Rep. 11, 438–444 (2010).
  Medline CASGoogle Scholar
• 161 Pollock JA, Larrea MD, Jasper JS, McDonnell DP, McCafferty DG. Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα -dependent and -independent manners. ACS Chem. Biol. 7(7), 1221–1231 (2012).
  Medline CASGoogle Scholar
• 162 Huang J, Sengupta R, Espejo AB et al. p53 is regulated by the lysine demethylase LSD1. Nature 449(7158), 105–108 (2007).
  Medline CASGoogle Scholar
• 163 Kontaki H, Talianidis I. Lysine methylation regulates E2F1-induced cell death. Mol. Cell 39(1), 152–160 (2010).
  Medline CASGoogle Scholar
• 164 Yang J, Huang J, Dasgupta M et al. Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes. Proc. Natl Acad. Sci. USA 107, 21499–21504 (2010).
  Medline CASGoogle Scholar
• 165 Cho HS, Suzuki T, Dohmae N et al. Demethylation of RB regulator MYPT1 by histone demethylase LSD1 promotes cell cycle progression in cancer cells. Cancer Res. 71(3), 655–660 (2011).
  Medline CASGoogle Scholar
• 166 Sugino N, Kawahara M, Tatsumi G et al. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. Leukemia doi:10.1038/leu.2017.59 (2017) (Epub ahead of print).
  MedlineGoogle Scholar
• 167 Ishikawa Y, Gamo K1, Yabuki M et al. A novel LSD1 inhibitor T-3775440 disrupts GFI1B-containing complex leading to transdifferentiation and impaired growth of AML cells. Mol. Cancer Ther. 16(2), 273–284 (2017).
  Medline CASGoogle Scholar
• 168 Yatim A, Benne C, Sobhian B et al. NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function. Mol. Cell 48, 445–458 (2012).
  Medline CASGoogle Scholar
• 169 Li Y, Deng C, Hu X et al. Dynamicinteraction between TAL1 oncoprotein and LSD1 regulates TAL1 function in hematopoiesis and leukemogenesis. Oncogene 31, 5007–5018 (2012).
  Medline CASGoogle Scholar
• 170 Pajtler KW, Weingarten C, Thor T et al. The KDM1A histone demethylase is a promising new target for the epigenetic therapy of medulloblastoma. Acta Neuropathol. Commun. 1, 19 (2013).
  MedlineGoogle Scholar
• 171 Lian SX, Shao YB, Liu HB et al. Lysine specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer. Oncotarget 6(32), 33065–33076 (2015).
  MedlineGoogle Scholar
• 172 Li Y, Wan X, Wei Y et al. LSD1-mediated epigenetic modification contributes to ovarian cancer cell migration and invasion. Oncol. Rep. 35(6), 3586–3592 (2016).
  Medline CASGoogle Scholar
• 173 Qin Y, Zhu W, Xu W et al. LSD1 sustains pancreatic cancer growth via maintaining HIF1α-dependent glycolytic process. Cancer Lett. 347(2), 225–232 (2014).
  Medline CASGoogle Scholar
• 174 Binda C, Valente S, Romanenghi M et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSDJ. Am. Chem. Soc. 132, 6827–6833 (2010). •• Reports co-treatment of tranylcypromine/Parnate analogs with retinoic acid to promote differentiation of AML cells.
  Medline CASGoogle Scholar
• 175 Schenk T, Chen WC, Göllner S et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012). •• Suggests all-trans retinoic acid and tranylcypromine as a combinatorial therapeutic strategy in AML.
  Medline CASGoogle Scholar
• 176 Baker JA, Fyfe MCT. WO2011106106A2 (2011).
  Google Scholar
• 177 Vankayalapati H, Sorna V, Warner SL et al. WO2014205213A1 (2014).
  Google Scholar
• 178 Fiskus W, Sharma S, Shah B et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia 28, 2155–2164 (2014).
  Medline CASGoogle Scholar
• 179 McGrath JP, Williamson KE, Balasubramanian S et al. Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid leukemia subtypes. Cancer Res. 76(7), 1975–1988 (2016).
  Medline CASGoogle Scholar
• 180 Zhang X, Lu F, Wang J et al. Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells. Cell Rep. 5(2), 445–457 (2013).
  Medline CASGoogle Scholar
• 181 Mohammad HP, Smitheman KN, Kamat CD et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28(1), 57–69 (2015). •• Reports a specific DNA methylation pattern as a predictive biomarker for sensitivity to LSD1 inhibitors.
  Medline CASGoogle Scholar
• 182 Goossens S, Peirs S, Van Loocke W et al. Oncogenic ZEB2 activation drives sensitivity toward KDM1A inhibition in T-cell acute lymphoblastic leukemia. Blood 129(8), 981–990 (2017).
  Medline CASGoogle Scholar
• 183 Mehdipour P, Santoro F, Minucci S. Epigenetic alterations in acute myeloid leukemias. FEBS J. 282(9), 1786–1800 (2015).
  Medline CASGoogle Scholar