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SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis

Oncogene volume 31, pages 4619–4629 (2012)Cite this article

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Abstract

The epithelial-to-mesenchymal transition (EMT) is a crucial program for the invasion and metastasis of epithelial tumors that involves loss of cell–cell adhesion and increased cell mobility; however, mechanisms underlying this transition are not fully elucidated. Here, we propose a novel mechanism through which the nicotinamide adenine dinucleotide-dependent histone deacetylase SIRT1 regulates EMT in prostate cancer cells through cooperation with the EMT inducing transcription factor ZEB1. We found that forced expression of SIRT1 in non-transformed PZ-HPV-7 prostate epithelial cells disrupts the epithelial morphology concomitant with decreased expression of the epithelial marker, E-cadherin, and increased expression of mesenchymal markers. In contrast, silencing SIRT1 in metastatic prostate tumor cells restores cell–cell adhesion and induces a shift toward an epithelial morphology concomitant with increased expression of E-cadherin and decreased expression of mesenchymal markers. We also found that SIRT1 has a physiologically relevant role in endogenous EMT induced by EGF signaling in prostate cancer cells. We propose that the regulation of EMT by SIRT1 involves modulation of, and cooperation with, the EMT inducing transcription factor ZEB1. Specifically, we show that SIRT1 silencing reduces expression of ZEB1 and that SIRT1 is recruited to the E-cadherin proximal promoter by ZEB1 to deacetylate histone H3 and to reduce binding of RNA polymerase II, ultimately suppressing E-cadherin transcription. We thus identify a necessary role for ZEB1 in SIRT1-mediated EMT. Finally, we show that reduction of SIRT1 decreases prostate cancer cell migration in vitro and metastasis in vivo in immunodeficient mice, which is largely independent of any general effects of SIRT1 on prostate cancer growth and survival. We therefore identify SIRT1 as a positive regulator of EMT and metastatic growth of prostate cancer cells and our findings implicate overexpressed SIRT1 as a potential therapeutic target to reverse EMT and to prevent prostate cancer progression.

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References

  1. Mimeault M, Batra SK . Recent advances on multiple tumorigenic cascades involved in prostatic cancer progression and targeting therapies. Carcinogenesis 2006; 27: 1–22.

    Article  CAS  PubMed  Google Scholar 

  2. Thiery JP . Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 2003; 15: 740–746.

    Article  CAS  PubMed  Google Scholar 

  3. Thiery JP, Sleeman JP . Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 2006; 7: 131–142.

    CAS  PubMed  Google Scholar 

  4. Savagner P . Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition. Bioessays 2001; 23: 912–923.

    Article  CAS  PubMed  Google Scholar 

  5. Voulgari A, Pintzas A . Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta 2009; 1796: 75–90.

    CAS  PubMed  Google Scholar 

  6. Ross JS, Figge HL, Bui HX, del Rosario AD, Fisher HA, Nazeer T et al. E-cadherin expression in prostatic carcinoma biopsies: correlation with tumor grade, DNA content, pathologic stage, and clinical outcome. Mod Pathol 1994; 7: 835–841.

    CAS  PubMed  Google Scholar 

  7. Richmond PJ, Karayiannakis AJ, Nagafuchi A, Kaisary AV, Pignatelli M . Aberrant E-cadherin and alpha-catenin expression in prostate cancer: correlation with patient survival. Cancer Res 1997; 57: 3189–3193.

    CAS  PubMed  Google Scholar 

  8. Peinado H, Portillo F, Cano A . Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 2004; 48: 365–375.

    Article  CAS  PubMed  Google Scholar 

  9. Wallerand H, Robert G, Pasticier G, Ravaud A, Ballanger P, Reiter RE et al. The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers(). Urol Oncol 2010; 28: 473–479.

    Article  CAS  PubMed  Google Scholar 

  10. Vandewalle C, Van Roy F, Berx G . The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 2009; 66: 773–787.

    Article  CAS  PubMed  Google Scholar 

  11. Sanchez-Tillo E, Lazaro A, Torrent R, M, Vaquero EC, Castells A et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 2010; 29: 3490–3500.

    Article  CAS  PubMed  Google Scholar 

  12. Graham TR, Zhau HE, Odero-Marah VA, Osunkoya AO, Kimbro KS, Tighiouart M et al. Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 2008; 68: 2479–2488.

    Article  CAS  PubMed  Google Scholar 

  13. Smith J . Human Sir2 and the ‘silencing’ of p53 activity. Trends Cell Biol 2002; 12: 404–406.

    Article  CAS  PubMed  Google Scholar 

  14. Bordone L, Guarente L . Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 2005; 6: 298–305.

    Article  CAS  PubMed  Google Scholar 

  15. Giannakou ME, Partridge L . The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 2004; 14: 408–412.

    Article  CAS  PubMed  Google Scholar 

  16. Guarente L . Sirtuins in aging and disease. Cold Spring Harb Symp Quant Biol 2007; 72: 483–488.

    Article  CAS  PubMed  Google Scholar 

  17. Guarente L, Picard F . Calorie restriction--the SIR2 connection. Cell 2005; 120: 473–482.

    Article  CAS  PubMed  Google Scholar 

  18. Liu T, Liu PY, Marshall GM . The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res 2009; 69: 1702–1705.

    Article  CAS  PubMed  Google Scholar 

  19. Saunders LR, Verdin E . Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 2007; 26: 5489–5504.

    Article  CAS  PubMed  Google Scholar 

  20. Yamamoto H, Schoonjans K, Auwerx J . Sirtuin functions in health and disease. Mol Endocrinol 2007; 21: 1745–1755.

    Article  CAS  PubMed  Google Scholar 

  21. Dai Y, Faller DV . Transcription Regulation by Class III Histone Deacetylases (HDACs)—Sirtuins. Transl Oncogenomics 2008; 3: 137–149.

    Google Scholar 

  22. Larue L, Bellacosa A . Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 2005; 24: 7443–7454.

    Article  CAS  PubMed  Google Scholar 

  23. Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415–428.

    Article  CAS  PubMed  Google Scholar 

  24. Moreno-Bueno G, Portillo F, Cano A . Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 2008; 27: 6958–6969.

    Article  CAS  PubMed  Google Scholar 

  25. Hajra KM, Ji X, Fearon ER . Extinction of E-cadherin expression in breast cancer via a dominant repression pathway acting on proximal promoter elements. Oncogene 1999; 18: 7274–7279.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 2005; 24: 2375–2385.

    Article  CAS  PubMed  Google Scholar 

  28. Michael E, Israel V . Tail vein assay of cancer metastasis. Curr Protoc Cell Biol 2001: 19.2.1–19.2.7.

  29. Kim EJ, Um SJ . SIRT1: roles in aging and cancer. BMB Rep 2008; 41: 751–756.

    Article  CAS  PubMed  Google Scholar 

  30. Baum B, Settleman J, Quinlan MP . Transitions between epithelial and mesenchymal states in development and disease. Semin Cell Dev Biol 2008; 19: 294–308.

    Article  CAS  PubMed  Google Scholar 

  31. Umbas R, Schalken JA, Aalders TW, Carter BS, Karthaus HFM, Schaafsma HE et al. Expression of the cellular adhesion molecule E-cadherin is reduced or absent in high-grade prostate cancer. Cancer Res 1992; 52: 5104–5109.

    CAS  PubMed  Google Scholar 

  32. Potente M, Ghaeni L, Baldessari D, Mostoslavsky R, Rossig L, Dequiedt F et al. SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev 2007; 21: 2644–2658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang Y, Zhang M, Dong H, Yong S, Li X, Olashaw N et al. Deacetylation of cortactin by SIRT1 promotes cell migration. Oncogene 2009; 28: 445–460.

    Article  CAS  PubMed  Google Scholar 

  34. Eades G, Yao Y, Yang M, Zhang Y, Chumsri S, Zhou Q . MiR-200a regulates SIRT1 and EMT-like transformation in mammary epithelial cells. J Biol Chem 2011; 286: 25992–26002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tryndyak VP, Beland FA, Pogribny IP . 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 2010; 126: 2575–2583.

    CAS  PubMed  Google Scholar 

  36. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res 2007; 67: 6612–6618.

    Article  CAS  PubMed  Google Scholar 

  37. Kwon HS, Ott M . The ups and downs of SIRT1. Trends Biochem Sci 2008; 33: 517–525.

    Article  CAS  PubMed  Google Scholar 

  38. Cha EJ, Noh SJ, Kwon KS, Kim CY, Park BH, Park HS et al. Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma. Clin Cancer Res 2009; 15: 4453–4459.

    Article  CAS  PubMed  Google Scholar 

  39. Jang KY, Hwang SH, Kwon KS, Kim KR, Choi HN, Lee NR et al. SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma. Am J Surg Pathol 2008; 32: 1523–1531.

    Article  PubMed  Google Scholar 

  40. Lee H, Kim KR, Noh SJ, Park HS, Kwon KS, Park BH et al. Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol 2011; 42: 204–213.

    Article  CAS  PubMed  Google Scholar 

  41. Tseng RC, Lee CC, Hsu HS, Tzao C, Wang YC . Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia 2009; 11: 763–770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ellis AL, Wang Z, Yu X, Mertz JE . Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein-Barr virus latent-lytic switch in a cell-type-specific manner. J Virol 84: 6139–6152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dai Y, Ngo D, Forman LW, Qin DC, Jacob J, Faller DV . Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol Endocrinol 2007; 21: 1807–1821.

    Article  CAS  PubMed  Google Scholar 

  44. Lacher MD, Shiina M, Chang P, Keller D, Tiirikainen MI, Korn WM . ZEB1 limits adenoviral infectability by transcriptionally repressing the Coxsackie virus and Adenovirus Receptor. Mol Cancer 2011; 10: 91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Dai Y, Ngo D, Jacob J, Forman LW, Faller DV . Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes. Carcinogenesis 2008; 29: 1725–1733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shtutman M, Levina E, Ohouo P, Baig M, Roninson IB . Cell adhesion molecule L1 disrupts E-cadherin-containing adherens junctions and increases scattering and motility of MCF7 breast carcinoma cells. Cancer Res 2006; 66: 11370–11380.

    Article  CAS  PubMed  Google Scholar 

  47. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res 2005; 33: 6566–6578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr F Picard (Laval University, Canada), Dr Michael Korn (USCF, CA), Dr M Ott (UCSF, CA) for providing plasmid constructs. We greatly thank the technical support in tumor cell s.c. injection from Dr Zhijun Luo (Boston University School of Medicine). We thank Lora Forman for the technical assistant (Boston University) and Christine Chiao (Boston University) for the proofreading of this manuscript. This work was supported by grants from the National Cancer Institute (1R21CA141036) (YD), the Clinical and Translational Science Institute award of NIH (UL1RR025771) (YD), the National Cancer Institute (CA101992) (DVF), the Karin Grunebaum Cancer Research Foundation (YD and DVF), the American Cancer Society (IRG-72-001-27-IRG) (YD), and the Department of Medicine Pilot Project Grant Award (YD).

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  1. V Byles and L Zhu: These authors contributed equally to this study.

Authors and Affiliations

  1. Cancer Center and Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    V Byles, L Zhu, J D Lovaas, L K Chmilewski, J Wang, D V Faller & Y Dai

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  1. V Byles
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Correspondence to Y Dai.

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Byles, V., Zhu, L., Lovaas, J. et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 31, 4619–4629 (2012). https://doi.org/10.1038/onc.2011.612

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