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HDAC inhibition impedes epithelial–mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer

Oncogene volume 35, pages 3781–3795 (2016)Cite this article

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Abstract

PI3K (phosphoinositide 3-kinase)/AKT and RAS/MAPK (mitogen-activated protein kinase) pathway coactivation in the prostate epithelium promotes both epithelial–mesenchymal transition (EMT) and metastatic castration-resistant prostate cancer (mCRPC), which is currently incurable. To study the dynamic regulation of the EMT process, we developed novel genetically defined cellular and in vivo model systems from which epithelial, EMT and mesenchymal-like tumor cells with Pten deletion and Kras activation can be isolated. When cultured individually, each population has the capacity to regenerate all three tumor cell populations, indicative of epithelial–mesenchymal plasticity. Despite harboring the same genetic alterations, mesenchymal-like tumor cells are resistant to PI3K and MAPK pathway inhibitors, suggesting that epigenetic mechanisms may regulate the EMT process, as well as dictate the heterogeneous responses of cancer cells to therapy. Among differentially expressed epigenetic regulators, the chromatin remodeling protein HMGA2 is significantly upregulated in EMT and mesenchymal-like tumors cells, as well as in human mCRPC. Knockdown of HMGA2, or suppressing HMGA2 expression with the histone deacetylase inhibitor LBH589, inhibits epithelial–mesenchymal plasticity and stemness activities in vitro and markedly reduces tumor growth and metastasis in vivo through successful targeting of EMT and mesenchymal-like tumor cells. Importantly, LBH589 treatment in combination with castration prevents mCRPC development and significantly prolongs survival following castration by enhancing p53 and androgen receptor acetylation and in turn sensitizing castration-resistant mesenchymal-like tumor cells to androgen deprivation therapy. Taken together, these findings demonstrate that cellular plasticity is regulated epigenetically, and that mesenchymal-like tumor cell populations in mCRPC that are resistant to conventional and targeted therapies can be effectively treated with the epigenetic inhibitor LBH589.

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References

  1. Siegel RL, Miller KD, Jemal A . Cancer statistics, 2015. Cancer J Clin 2015; 65: 5–29.

    Article  Google Scholar 

  2. Attard G, de Bono JS . Translating scientific advancement into clinical benefit for castration-resistant prostate cancer patients. Clin Cancer Res 2011; 17: 3867–3875.

    Article  CAS  PubMed  Google Scholar 

  3. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187–1197.

    CAS  PubMed  Google Scholar 

  5. Rescigno P, Buonerba C, Bellmunt J, Sonpavde G, De Placido S, Di Lorenzo G . New perspectives in the therapy of castration resistant prostate cancer. Curr Drug Targets 2012; 13: 1676–1686.

    Article  PubMed  Google Scholar 

  6. Shah RB, Mehra R, Chinnaiyan AM, Shen R, Ghosh D, Zhou M et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res 2004; 64: 9209–9216.

    Article  CAS  PubMed  Google Scholar 

  7. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baca SC, Garraway LA . The genomic landscape of prostate cancer. Front Endocrinol 2012; 3: 69.

    Article  Google Scholar 

  9. Brannon AR, Sawyers CL . ‘N of 1’ case reports in the era of whole-genome sequencing. J Clin Invest 2013; 123: 4568–4570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest 2013; 123: 4918–4922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tanaka H, Kono E, Tran CP, Miyazaki H, Yamashiro J, Shimomura T et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med 2010; 16: 1414–1420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun Y, Wang BE, Leong KG, Yue P, Li L, Jhunjhunwala S et al. Androgen deprivation causes epithelial–mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res 2012; 72: 527–536.

    Article  CAS  PubMed  Google Scholar 

  13. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD et al. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res 2011; 9: 997–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bitting RL, Schaeffer D, Somarelli JA, Garcia-Blanco MA, Armstrong AJ . The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metast Rev 2014; 33: 441–468.

    Article  CAS  Google Scholar 

  15. Marin-Aguilera M, Codony-Servat J, Reig O, Lozano JJ, Fernandez PL, Pereira MV et al. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol Cancer Therap 2014; 13: 1270–1284.

    Article  CAS  Google Scholar 

  16. Mulholland DJ, Kobayashi N, Ruscetti M, Zhi A, Tran LM, Huang J et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 2012; 72: 1878–1889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ruscetti M, Quach B, Dadashian EL, Mulholland DJ, Wu H . Tracking and functional characterization of epithelial–mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Cancer Res 2015; 75: 2149–2159.

    Article  Google Scholar 

  18. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tam WL, Weinberg RA . The epigenetics of epithelial–mesenchymal plasticity in cancer. Nat Med 2013; 19: 1438–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fusco A, Fedele M . Roles of HMGA proteins in cancer. Nat Rev Cancer 2007; 7: 899–910.

    Article  CAS  PubMed  Google Scholar 

  21. Nishino J, Kim I, Chada K, Morrison SJ . Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf Expression. Cell 2008; 135: 227–239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Li O, Vasudevan D, Davey CA, Droge P . High-level expression of DNA architectural factor HMGA2 and its association with nucleosomes in human embryonic stem cells. Genesis 2006; 44: 523–529.

    Article  CAS  PubMed  Google Scholar 

  23. Rommel B, Rogalla P, Jox A, Kalle CV, Kazmierczak B, Wolf J et al. HMGI-C, a member of the high mobility group family of proteins, is expressed in hematopoietic stem cells and in leukemic cells. Leuk Lymphoma 1997; 26: 603–607.

    Article  CAS  PubMed  Google Scholar 

  24. Zong Y, Huang J, Sankarasharma D, Morikawa T, Fukayama M, Epstein JI et al. Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling. Proc Natl Acad Sci USA 2012; 109: E3395–E3404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Watanabe S, Ueda Y, Akaboshi S, Hino Y, Sekita Y, Nakao M . HMGA2 maintains oncogenic RAS-induced epithelial–mesenchymal transition in human pancreatic cancer cells. Am J Pathol 2009; 174: 854–868.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luo Y, Li W, Liao H . HMGA2 induces epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Oncol Lett 2013; 5: 1353–1356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sun M, Song CX, Huang H, Frankenberger CA, Sankarasharma D, Gomes S et al. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc Natl Acad Sci USA 2013; 110: 9920–9925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zha L, Wang Z, Tang W, Zhang N, Liao G, Huang Z . Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells. Mol Cell Biochem 2012; 364: 243–251.

    Article  CAS  PubMed  Google Scholar 

  29. Gu L, Frommel SC, Oakes CC, Simon R, Grupp K, Gerig CY et al. BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence. Nat Genet 2015; 47: 22–30.

    Article  CAS  PubMed  Google Scholar 

  30. Ferguson M, Henry PA, Currie RA . Histone deacetylase inhibition is associated with transcriptional repression of the Hmga2 gene. Nucleic Acids Res 2003; 31: 3123–3133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lee S, Jung JW, Park SB, Roh K, Lee SY, Kim JH et al. Histone deacetylase regulates high mobility group A2-targeting microRNAs in human cord blood-derived multipotent stem cell aging. Cell Mol Life Sci 2011; 68: 325–336.

    Article  CAS  PubMed  Google Scholar 

  32. Luo J, Li M, Tang Y, Laszkowska M, Roeder RG, Gu W . Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc Natl Acad Sci USA 2004; 101: 2259–2264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gu W, Roeder RG . Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997; 90: 595–606.

    Article  CAS  PubMed  Google Scholar 

  34. Lei Q, Jiao J, Xin L, Chang CJ, Wang S, Gao J et al. NKX3.1 stabilizes p53, inhibits AKT activation, and blocks prostate cancer initiation caused by PTEN loss. Cancer Cell 2006; 9: 367–378.

    Article  CAS  PubMed  Google Scholar 

  35. Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, Jiao J et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 2003; 4: 209–221.

    Article  CAS  PubMed  Google Scholar 

  36. Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H . Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res 2009; 69: 8555–8562.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D et al. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol 2003; 23: 8563–8575.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Haelens A, Tanner T, Denayer S, Callewaert L, Claessens F . The hinge region regulates DNA binding, nuclear translocation, and transactivation of the androgen receptor. Cancer Res 2007; 67: 4514–4523.

    Article  CAS  PubMed  Google Scholar 

  39. Gaughan L, Logan IR, Cook S, Neal DE, Robson CN . Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J Biol Chem 2002; 277: 25904–25913.

    Article  CAS  PubMed  Google Scholar 

  40. Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC et al. Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell 2012; 21: 227–239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov 2014; 4: 816–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rathkopf D, Wong BY, Ross RW, Anand A, Tanaka E, Woo MM et al. A phase I study of oral panobinostat alone and in combination with docetaxel in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 2010; 66: 181–189.

    Article  CAS  PubMed  Google Scholar 

  43. Molife LR, Attard G, Fong PC, Karavasilis V, Reid AH, Patterson S et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC). Ann Oncol 2010; 21: 109–113.

    Article  CAS  PubMed  Google Scholar 

  44. Bradley D, Rathkopf D, Dunn R, Stadler WM, Liu G, Smith DC et al. Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: a study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer 2009; 115: 5541–5549.

    Article  CAS  PubMed  Google Scholar 

  45. Rathkopf DE, Picus J, Hussain A, Ellard S, Chi KN, Nydam T et al. A phase 2 study of intravenous panobinostat in patients with castration-resistant prostate cancer. Cancer Chemother Pharmacol 2013; 72: 537–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Welsbie DS, Xu J, Chen Y, Borsu L, Scher HI, Rosen N et al. Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer. Cancer Res 2009; 69: 958–966.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu X, Gomez-Pinillos A, Liu X, Johnson EM, Ferrari AC . Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Puralpha-mediated decrease in androgen receptor levels. Prostate 2010; 70: 179–189.

    CAS  PubMed  Google Scholar 

  48. Langelotz C, Schmid P, Jakob C, Heider U, Wernecke KD, Possinger K et al. Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer. Br J Cancer 2003; 88: 1406–1410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 2011; 473: 101–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 2005; 307: 1098–1101.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank members of the Hong Wu lab for their critical comments and suggestions. We also thank Drs Yang Zong and Owen Witte for generously supplying us with HMGA2 antibodies, and Dr Shumin Wu for supplying protein lysates from mouse ES cells. MR was supported by NIH T32 CA009056. WG was supported by a General Financial Grant from the China Postdoctoral Science Foundation (2015M570010), and in part by the Postdoctoral Fellowship of Peking-Tsinghua Center for Life Sciences. DJM was supported by NIH F32 CA112988-01, CIRM TG2-01169 and a Prostate Cancer Foundation Young Investigator Award. This work has been supported, in part, by awards from the Prostate Cancer Foundation (to HW), and grants from the NIH (P50 CA097186 and P01 CA163227 to PSN, P50 CA092131 to YX and HW, and R01 CA107166, RO1 CA121110 and U01 CA164188 to HW).

Author information

Author notes

  1. M Ruscetti

    Present address: 6Current address: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.,

  2. D J Mulholland

    Present address: 7Current address: Division of Hematology and Medical Oncology, Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.,

  3. J W Park

    Present address: 8Current address: Computer Engineering and Computer Science, KBRIN Bioinformatics Core, University of Louisville, Louisville, KY, USA.,

Authors and Affiliations

  1. Molecular Biology Institute, UCLA, Los Angeles, CA, USA

    M Ruscetti & H Wu

  2. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA

    M Ruscetti, E L Dadashian, B Quach, D J Mulholland, L M Tran, N Kobayashi & H Wu

  3. School of Life Sciences, Peking University, Beijing, China

    W Guo & H Wu

  4. Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA, USA

    J W Park & Y Xing

  5. Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    D Bianchi-Frias & P S Nelson

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Correspondence to H Wu.

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Ruscetti, M., Dadashian, E., Guo, W. et al. HDAC inhibition impedes epithelial–mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35, 3781–3795 (2016). https://doi.org/10.1038/onc.2015.444

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