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Cell cycle-coupled expansion of AR activity promotes cancer progression

Abstract

The androgen receptor (AR) is required for prostate cancer (PCa) survival and progression, and ablation of AR activity is the first line of therapeutic intervention for disseminated disease. While initially effective, recurrent tumors ultimately arise for which there is no durable cure. Despite the dependence of PCa on AR activity throughout the course of disease, delineation of the AR-dependent transcriptional network that governs disease progression remains elusive, and the function of AR in mitotically active cells is not well understood. Analyzing AR activity as a function of cell cycle revealed an unexpected and highly expanded repertoire of AR-regulated gene networks in actively cycling cells. New AR functions segregated into two major clusters: those that are specific to cycling cells and retained throughout the mitotic cell cycle ('Cell Cycle Common'), versus those that were specifically enriched in a subset of cell cycle phases ('Phase Restricted'). Further analyses identified previously unrecognized AR functions in major pathways associated with clinical PCa progression. Illustrating the impact of these unmasked AR-driven pathways, dihydroceramide desaturase 1 was identified as an AR-regulated gene in mitotically active cells that promoted pro-metastatic phenotypes, and in advanced PCa proved to be highly associated with development of metastases, recurrence after therapeutic intervention and reduced overall survival. Taken together, these findings delineate AR function in mitotically active tumor cells, thus providing critical insight into the molecular basis by which AR promotes development of lethal PCa and nominate new avenues for therapeutic intervention.

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References

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

    Article  Google Scholar 

  2. Knudsen KE, Penning TM . Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab 2010; 21: 315–324.

    CAS  Article  Google Scholar 

  3. Knudsen KE, Scher HI . Starving the addiction: new opportunities for durable suppression of AR signaling in prostate cancer. Clin Cancer Res 2009; 15: 4792–4798.

    CAS  Article  Google Scholar 

  4. Beekman KW, Hussain M . Hormonal approaches in prostate cancer: application in the contemporary prostate cancer patient. Urol Oncol 2008; 26: 415–419.

    CAS  Article  Google Scholar 

  5. Knudsen KE, Kelly WK . Outsmarting androgen receptor: creative approaches for targeting aberrant androgen signaling in advanced prostate cancer. Expert Rev Endocrinol Metab 2011; 6: 483–493.

    CAS  Article  Google Scholar 

  6. Yuan X, Balk SP . Mechanisms mediating androgen receptor reactivation after castration. Urol Oncol 2009; 27: 36–41.

    CAS  Article  Google Scholar 

  7. Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP . Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene 2014; 33: 2815–2825.

    CAS  Article  Google Scholar 

  8. Barfeld SJ, Itkonen HM, Urbanucci A, Mills IG . Androgen-regulated metabolism and biosynthesis in prostate cancer. Endocr Relat Cancer 2014; 21: T57–T66.

    Article  Google Scholar 

  9. Massie CE, Lynch A, Ramos-Montoya A, Boren J, Stark R, Fazli L et al. The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis. EMBO J 2011; 30: 2719–2733.

    CAS  Article  Google Scholar 

  10. Xu Y, Chen SY, Ross KN, Balk SP . Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res 2006; 66: 7783–7792.

    CAS  Article  Google Scholar 

  11. Wang Q, Li W, Zhang Y, Yuan X, Xu K, Yu J et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009; 138: 245–256.

    CAS  Article  Google Scholar 

  12. Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ, Janne OA et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res 2009; 69: 8141–8149.

    CAS  Article  Google Scholar 

  13. Nelson PS, Clegg N, Arnold H, Ferguson C, Bonham M, White J et al. The program of androgen-responsive genes in neoplastic prostate epithelium. Proc Natl Acad Sci USA 2002; 99: 11890–11895.

    CAS  Article  Google Scholar 

  14. Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C et al. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 2010; 120: 4478–4492.

    CAS  Article  Google Scholar 

  15. Mallik I, Davila M, Tapia T, Schanen B, Chakrabarti R . Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. Biochim Biophys Acta 2008; 1783: 1737–1744.

    CAS  Article  Google Scholar 

  16. Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov 2013; 3: 1254–1271.

    CAS  Article  Google Scholar 

  17. Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov 2013; 3: 1245–1253.

    CAS  Article  Google Scholar 

  18. Nauseef JT, Henry MD . Epithelial-to-mesenchymal transition in prostate cancer: paradigm or puzzle? Nat Rev Urol 2011; 8: 428–439.

    Article  Google Scholar 

  19. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer 2007; 7: 256–269.

    CAS  Article  Google Scholar 

  20. Schmidt D, Wilson MD, Spyrou C, Brown GD, Hadfield J, Odom DT . ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions. Methods 2009; 48: 240–248.

    CAS  Article  Google Scholar 

  21. Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007; 27: 380–392.

    Article  Google Scholar 

  22. Pomerantz MM, Li F, Takeda DY, Lenci R, Chonkar A, Chabot M et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat Genet 2015; 47: 1346–1351.

    CAS  Article  Google Scholar 

  23. Grabowska MM, Elliott AD, DeGraff DJ, Anderson PD, Anumanthan G, Yamashita H et al. NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression. Mol Endocrinol 2014; 28: 949–964.

    Article  Google Scholar 

  24. Bubulya A, Wise SC, Shen XQ, Burmeister LA, Shemshedini L . c-Jun can mediate androgen receptor-induced transactivation. J Biol Chem 1996; 271: 24583–24589.

    CAS  Article  Google Scholar 

  25. Chen SY, Cai C, Fisher CJ, Zheng Z, Omwancha J, Hsieh CL et al. c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation. Oncogene 2006; 25: 7212–7223.

    CAS  Article  Google Scholar 

  26. 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.

    CAS  Article  Google Scholar 

  27. Lord CJ, Ashworth A . The DNA damage response and cancer therapy. Nature 2012; 481: 287–294.

    CAS  Article  Google Scholar 

  28. Augello MA, Den RB, Knudsen KE . AR function in promoting metastatic prostate cancer. Cancer Metastasis Rev 2014; 33: 399–411.

    CAS  Article  Google Scholar 

  29. Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL et al. DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell 2015; 28: 97–113.

    CAS  Article  Google Scholar 

  30. Williams K, Ghosh R, Giridhar PV, Gu G, Case T, Belcher SM et al. Inhibition of stathmin1 accelerates the metastatic process. Cancer Res 2012; 72: 5407–5417.

    CAS  Article  Google Scholar 

  31. Liu W, Yue F, Zheng M, Merlot A, Bae DH, Huang M et al. The proto-oncogene c-Src and its downstream signaling pathways are inhibited by the metastasis suppressor, NDRG1. Oncotarget 2015; 6: 8851–8874.

    PubMed  PubMed Central  Google Scholar 

  32. Lazarini M, Traina F, Machado-Neto JA, Barcellos KS, Moreira YB, Brandao MM et al. ARHGAP21 is a RhoGAP for RhoA and RhoC with a role in proliferation and migration of prostate adenocarcinoma cells. Biochim Biophys Acta 2013; 1832: 365–374.

    CAS  Article  Google Scholar 

  33. Jian H, Zhao Y, Liu B, Lu S . SEMA4B inhibits growth of non-small cell lung cancer in vitro and in vivo. Cell Signal 2015; 27: 1208–1213.

    CAS  Article  Google Scholar 

  34. Zhou W, Ye XL, Sun ZJ, Ji XD, Chen HX, Xie D . Overexpression of degenerative spermatocyte homolog 1 up-regulates the expression of cyclin D1 and enhances metastatic efficiency in esophageal carcinoma Eca109 cells. Mol Carcinog 2009; 48: 886–894.

    CAS  Article  Google Scholar 

  35. Chalfant CE, Spiegel S . Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 2005; 118 (Pt 20): 4605–4612.

    CAS  Article  Google Scholar 

  36. Gangoiti P, Granado MH, Wang SW, Kong JY, Steinbrecher UP, Gomez-Munoz A . Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways. Cell Signal 2008; 20: 726–736.

    CAS  Article  Google Scholar 

  37. Martinez ED, Danielsen M . Loss of androgen receptor transcriptional activity at the G(1)/S transition. J Biol Chem 2002; 277: 29719–29729.

    CAS  Article  Google Scholar 

  38. Balk SP, Knudsen KE . AR, the cell cycle, and prostate cancer. Nucl Recept Signal 2008; 6: e001.

    Article  Google Scholar 

  39. Zaret KS, Carroll JS . Pioneer transcription factors: establishing competence for gene expression. Genes Dev 2011; 25: 2227–2241.

    CAS  Article  Google Scholar 

  40. He B, Lanz RB, Fiskus W, Geng C, Yi P, Hartig SM et al. GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex. Proc Natl Acad Sci USA 2014; 111: 18261–18266.

    CAS  Article  Google Scholar 

  41. Yun EJ, Baek ST, Xie D, Tseng SF, Dobin T, Hernandez E et al. DAB2IP regulates cancer stem cell phenotypes through modulating stem cell factor receptor and ZEB1. Oncogene 2015; 34: 2741–2752.

    CAS  Article  Google Scholar 

  42. Gudmundsdottir K, Ashworth A . The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 2006; 25: 5864–5874.

    CAS  Article  Google Scholar 

  43. Mullan PB, Quinn JE, Harkin DP . The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 2006; 25: 5854–5863.

    CAS  Article  Google Scholar 

  44. Fu Y, Sinha M, Peterson CL, Weng Z . The insulator binding protein CTCF positions 20 nucleosomes around its binding sites across the human genome. PLoS Genet 2008; 4: e1000138.

    Article  Google Scholar 

  45. Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A et al. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 2011; 30: 3962–3976.

    CAS  Article  Google Scholar 

  46. Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 2013; 23: 35–47.

    CAS  Article  Google Scholar 

  47. Dang CV . MYC on the path to cancer. Cell 2012; 149: 22–35.

    CAS  Article  Google Scholar 

  48. Gurel B, Iwata T, Koh CM, Jenkins RB, Lan F, Van Dang C et al. Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol 2008; 21: 1156–1167.

    CAS  Article  Google Scholar 

  49. Palaskas N, Larson SM, Schultz N, Komisopoulou E, Wong J, Rohle D et al. 18 F-fluorodeoxy-glucose positron emission tomography marks MYC-overexpressing human basal-like breast cancers. Cancer Res 2011; 71: 5164–5174.

    CAS  Article  Google Scholar 

  50. Fan L, Peng G, Sahgal N, Fazli L, Gleave M, Zhang Y et al. Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene 2015; 35: 2441–2452.

    Article  Google Scholar 

  51. Barfeld SJ, Fazli L, Persson M, Marjavaara L, Urbanucci A, Kaukoniemi KM et al. Myc-dependent purine biosynthesis affects nucleolar stress and therapy response in prostate cancer. Oncotarget 2015; 6: 12587–12602.

    Article  Google Scholar 

  52. Schrecengost RS, Dean JL, Goodwin JF, Schiewer MJ, Urban MW, Stanek TJ et al. USP22 regulates oncogenic signaling pathways to drive lethal cancer progression. Cancer Res 2014; 74: 272–286.

    CAS  Article  Google Scholar 

  53. Lim JT, Mansukhani M, Weinstein IB . Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells. Proc Natl Acad Sci USA 2005; 102: 5156–5161.

    CAS  Article  Google Scholar 

  54. Burd CJ, Petre CE, Morey LM, Wang Y, Revelo MP, Haiman CA et al. Cyclin D1b variant influences prostate cancer growth through aberrant androgen receptor regulation. Proc Natl Acad Sci USA 2006; 103: 2190–2195.

    CAS  Article  Google Scholar 

  55. Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A et al. Cyclin D1 is a selective modifier of androgen-dependent signaling and androgen receptor function. J Biol Chem 2011; 286: 8117–8127.

    CAS  Article  Google Scholar 

  56. Knudsen KE, Cavenee WK, Arden KC . D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability. Cancer Res 1999; 59: 2297–2301.

    CAS  PubMed  Google Scholar 

  57. Augello MA, Berman-Booty LD, Carr R 3rd, Yoshida A, Dean JL, Schiewer MJ et al. Consequence of the tumor-associated conversion to cyclin D1b. EMBO Mol Med 2015; 7: 628–647.

    CAS  Article  Google Scholar 

  58. Yamamoto A, Hashimoto Y, Kohri K, Ogata E, Kato S, Ikeda K et al. Cyclin E as a coactivator of the androgen receptor. J Cell Biol 2000; 150: 873–880.

    CAS  Article  Google Scholar 

  59. Chua SS, Ma Z, Ngan E, Tsai SY . Cdc25B as a steroid receptor coactivator. Vitam Horm 2004; 68: 231–256.

    CAS  Article  Google Scholar 

  60. Koryakina Y, Knudsen KE, Gioeli D . Cell-cycle-dependent regulation of androgen receptor function. Endocr Relat Cancer 2015; 22: 249–264.

    CAS  Article  Google Scholar 

  61. Comstock CE, Augello MA, Goodwin JF, de Leeuw R, Schiewer MJ, Ostrander WF Jr et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene 2013; 32: 5481–5491.

    CAS  Article  Google Scholar 

  62. Venant H, Rahmaniyan M, Jones EE, Lu P, Lilly MB, Garrett-Mayer E et al. The Sphingosine Kinase 2 inhibitor ABC294640 reduces the growth of prostate cancer cells and results in accumulation of dihydroceramides in vitro and in vivo. Mol Cancer Ther 2015; 14: 2744–2752.

    CAS  Article  Google Scholar 

  63. Erho N, Crisan A, Vergara IA, Mitra AP, Ghadessi M, Buerki C et al. Discovery and validation of a prostate cancer genomic classifier that predicts early metastasis following radical prostatectomy. PLoS One 2013; 8: e66855.

    CAS  Article  Google Scholar 

  64. Karnes RJ, Bergstralh EJ, Davicioni E, Ghadessi M, Buerki C, Mitra AP et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol 2013; 190: 2047–2053.

    CAS  Article  Google Scholar 

  65. Prensner JR, Zhao S, Erho N, Schipper M, Iyer MK, Dhanasekaran SM et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol 2014; 15: 1469–1480.

    CAS  Article  Google Scholar 

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Acknowledgements

We gratefully thank Mandeep Takhar for her assistance in providing microarray data analysis, K Knudsen lab members for their input, Bin Fang for assistance in creation of motif diagrams and E Schade for graphical support and expertise. This work was supported by grants to WL (R01HG007538 and R01CA193466), SGZ by the PCF, and to KEK by grants from the NCI (CA159945, CA176401), P30-CA056036, and in part by a grant to KEK with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.

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McNair, C., Urbanucci, A., Comstock, C. et al. Cell cycle-coupled expansion of AR activity promotes cancer progression. Oncogene 36, 1655–1668 (2017). https://doi.org/10.1038/onc.2016.334

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