Skip to main content
SpringerLink
Log in

Roles of Androgen Receptor Coregulators and Cell Signaling in the Regulation of Androgen-Responsive Genes

  • Chapter
  • First Online:
Androgen-Responsive Genes in Prostate Cancer

  • 1074 Accesses

Abstract

Androgen receptor (AR) is a member of the ligand activated transcription factor family. Its function is regulated by a complex network of coregulatory proteins and cell signaling pathways. AR is a key transcription factor in healthy prostate function and during neoplastic transformation. In normal prostate, it regulates prostate secretory function, stimulates epithelial cell renewal, and maintains the cells in a differentiated state. However, under certain circumstances AR function loses its differentiating thrust and proliferative function becomes dominant. Changes in coregulator expression and alteration of cell signaling pathways may contribute to changes in androgen-dependent AR action and play a major role in castration resistant prostate cancer (CRPC).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. He B, Kemppainen JA, Voegel JJ, Gronemeyer H, Wilson EM (1999) Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain. J Biol Chem 274:37219–37225

    Article  PubMed  CAS  Google Scholar 

  2. Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266

    Article  PubMed  CAS  Google Scholar 

  3. Onate SA, Tsai SY, Tsai MJ, O’Malley BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270:1354–1357

    Article  PubMed  CAS  Google Scholar 

  4. Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, Privalsky ML, Nakatani Y, Evans RM (1997) Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90:569–580

    Article  PubMed  CAS  Google Scholar 

  5. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ et al (1997) Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389:194–198

    Article  PubMed  CAS  Google Scholar 

  6. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B et al (2010) Integrative genomic profiling of human prostate cancer. Cancer Cell 18:11–22

    Article  PubMed  CAS  Google Scholar 

  7. Agoulnik IU, Vaid A, Nakka M, Alvarado M, Bingman WE 3rd, Erdem H, Frolov A, Smith CL, Ayala GE, Ittmann MM et al (2006) Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res 66:10594–10602

    Article  PubMed  CAS  Google Scholar 

  8. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, Wilson EM (2001) A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Res 61:4315–4319

    PubMed  CAS  Google Scholar 

  9. Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, Sauter G, Kallioniemi OP, Trent JM, Meltzer PS (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277:965–968

    Article  PubMed  CAS  Google Scholar 

  10. Yan J, Erdem H, Li R, Cai Y, Ayala G, Ittmann M, Yu-Lee LY, Tsai SY, Tsai MJ (2008) Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression. Cancer Res 68:5460–5468

    Article  PubMed  CAS  Google Scholar 

  11. Zhou HJ, Yan J, Luo W, Ayala G, Lin SH, Erdem H, Ittmann M, Tsai SY, Tsai MJ (2005) SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res 65:7976–7983

    PubMed  CAS  Google Scholar 

  12. Agoulnik IU, Weigel NL (2009) Coactivator selective regulation of androgen receptor activity. Steroids 74:669–674

    Article  PubMed  CAS  Google Scholar 

  13. Yan J, Yu CT, Ozen M, Ittmann M, Tsai SY, Tsai MJ (2006) Steroid receptor coactivator-3 and activator protein-1 coordinately regulate the transcription of components of the insulin-like growth factor/AKT signaling pathway. Cancer Res 66:11039–11046

    Article  PubMed  CAS  Google Scholar 

  14. Zhou G, Hashimoto Y, Kwak I, Tsai SY, Tsai MJ (2003) Role of the steroid receptor coactivator SRC-3 in cell growth. Mol Cell Biol 23:7742–7755

    Article  PubMed  CAS  Google Scholar 

  15. Li C, Ao J, Fu J, Lee DF, Xu J, Lonard D, O’Malley BW (2011) Tumor-suppressor role for the SPOP ubiquitin ligase in signal-dependent proteolysis of the oncogenic co-activator SRC-3/AIB1. Oncogene 30:4350–4364

    Article  PubMed  CAS  Google Scholar 

  16. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, White TA, Stojanov P, Van Allen E, Stransky N et al (2012) Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 44:685–689

    Article  PubMed  CAS  Google Scholar 

  17. Agoulnik IU, Vaid A, Bingman WE 3rd, Erdeme H, Frolov A, Smith CL, Ayala G, Ittmann MM, Weigel NL (2005) Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression. Cancer Res 65:7959–7967

    PubMed  CAS  Google Scholar 

  18. Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG (2000) p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem 275:20853–20860

    Article  PubMed  CAS  Google Scholar 

  19. Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C et al (2003) Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol 23:8563–8575

    Article  PubMed  CAS  Google Scholar 

  20. Ianculescu I, Wu DY, Siegmund KD, Stallcup MR (2012) Selective roles for cAMP response element-binding protein binding protein and p300 protein as coregulators for androgen-regulated gene expression in advanced prostate cancer cells. J Biol Chem 287:4000–4013

    Article  PubMed  CAS  Google Scholar 

  21. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP (1999) Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 41:127–133

    Article  PubMed  CAS  Google Scholar 

  22. Hoosein N, Abdul M, McCabe R, Gero E, Deftos L, Banks M, Hodges S, Finn L, Logothetis C (1995) Clinical significance of elevation in neuroendocrine factors and interleukin-6 in metastatic prostate cancer. Urol Oncol 1:246–251

    Article  PubMed  CAS  Google Scholar 

  23. Debes JD, Schmidt LJ, Huang H, Tindall DJ (2002) p300 mediates androgen-independent transactivation of the androgen receptor by interleukin 6. Cancer Res 62:5632–5636

    PubMed  CAS  Google Scholar 

  24. Clark EL, Coulson A, Dalgliesh C, Rajan P, Nicol SM, Fleming S, Heer R, Gaughan L, Leung HY, Elliott DJ et al (2008) The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Res 68:7938–7946

    Article  PubMed  CAS  Google Scholar 

  25. Agoulnik IU, Krause WC, Bingman WE 3rd, Rahman HT, Amrikachi M, Ayala GE, Weigel NL (2003) Repressors of androgen and progesterone receptor action. J Biol Chem 278:31136–31148

    Article  PubMed  CAS  Google Scholar 

  26. Shang Y, Myers M, Brown M (2002) Formation of the androgen receptor transcription complex. Mol Cell 9:601–610

    Article  PubMed  CAS  Google Scholar 

  27. Yu J, Palmer C, Alenghat T, Li Y, Kao G, Lazar MA (2006) The corepressor silencing mediator for retinoid and thyroid hormone receptor facilitates cellular recovery from DNA double-strand breaks. Cancer Res 66:9316–9322

    Article  PubMed  CAS  Google Scholar 

  28. Furuya F, Guigon CJ, Zhao L, Lu C, Hanover JA, Cheng SY (2007) Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling. Mol Cell Biol 27:6116–6126

    Article  PubMed  CAS  Google Scholar 

  29. Ghisletti S, Huang W, Jepsen K, Benner C, Hardiman G, Rosenfeld MG, Glass CK (2009) Cooperative NCoR/SMRT interactions establish a corepressor-based strategy for integration of inflammatory and anti-inflammatory signaling pathways. Genes Dev 23:681–693

    Article  PubMed  CAS  Google Scholar 

  30. Gioeli D, Paschal BM (2012) Post-translational modification of the androgen receptor. Mol Cell Endocrinol 352:70–78

    Article  PubMed  CAS  Google Scholar 

  31. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J et al (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem 277:29304–29314

    Article  PubMed  CAS  Google Scholar 

  32. Gordon V, Bhadel S, Wunderlich W, Zhang J, Ficarro SB, Mollah SA, Shabanowitz J, Hunt DF, Xenarios I, Hahn WC et al (2010) CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol 24:2267–2280

    Article  PubMed  CAS  Google Scholar 

  33. Chen S, Gulla S, Cai C, Balk SP (2012) Androgen receptor serine 81 phosphorylation mediates chromatin binding and transcriptional activation. J Biol Chem 287:8571–8583

    Article  PubMed  CAS  Google Scholar 

  34. Lee EC, Frolov A, Li R, Ayala G, Greenberg NM (2006) Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 66:4996–5002

    Article  PubMed  CAS  Google Scholar 

  35. Shu SK, Liu Q, Coppola D, Cheng JQ (2010) Phosphorylation and activation of androgen receptor by Aurora-A. J Biol Chem 285:33045–33053

    Article  PubMed  CAS  Google Scholar 

  36. Ayala G, Thompson T, Yang G, Frolov A, Li R, Scardino P, Ohori M, Wheeler T, Harper W (2004) High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence. Clin Cancer Res 10:6572–6578

    Article  PubMed  CAS  Google Scholar 

  37. Miyamoto H, Altuwaijri S, Cai Y, Messing EM, Chang C (2005) Inhibition of the Akt, cyclooxygenase-2, and matrix metalloproteinase-9 pathways in combination with androgen deprivation therapy: potential therapeutic approaches for prostate cancer. Mol Carcinog 44:1–10

    Article  PubMed  CAS  Google Scholar 

  38. Wang Y, Kreisberg JI, Ghosh PM (2007) Cross-talk between the androgen receptor and the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer. Curr Cancer Drug Targets 7:591–604

    Article  PubMed  CAS  Google Scholar 

  39. Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY, Chang C (2003) Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem 278:50902–50907

    Article  PubMed  CAS  Google Scholar 

  40. Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A 98:7200–7205

    Article  PubMed  CAS  Google Scholar 

  41. Taneja SS, Ha S, Swenson NK, Huang HY, Lee P, Melamed J, Shapiro E, Garabedian MJ, Logan SK (2005) Cell-specific regulation of androgen receptor phosphorylation in vivo. J Biol Chem 280:40916–40924

    Article  PubMed  CAS  Google Scholar 

  42. Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH, Hung MC (2000) HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res 60:6841–6845

    PubMed  CAS  Google Scholar 

  43. Cinar B, Mukhopadhyay NK, Meng G, Freeman MR (2007) Phosphoinositide 3-kinase-­independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. J Biol Chem 282:29584–29593

    Article  PubMed  CAS  Google Scholar 

  44. Hodgson MC, Shao LJ, Frolov A, Li R, Peterson LE, Ayala G, Ittmann MM, Weigel NL, Agoulnik IU (2011) Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res 71:572–582

    Article  PubMed  CAS  Google Scholar 

  45. Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, Arora VK, Le C, Koutcher J, Scher H et al (2011) Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 19:575–586

    Article  PubMed  CAS  Google Scholar 

  46. Minner S, Jessen B, Stiedenroth L, Burandt E, Kollermann J, Mirlacher M, Erbersdobler A, Eichelberg C, Fisch M, Brummendorf TH et al (2010) Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res 16:1553–1560

    Article  PubMed  CAS  Google Scholar 

  47. Abreu-Martin MT, Chari A, Palladino AA, Craft NA, Sawyers CL (1999) Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer. Mol Cell Biol 19:5143–5154

    PubMed  CAS  Google Scholar 

  48. Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ (1999) Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res 59:279–284

    PubMed  CAS  Google Scholar 

  49. Agoulnik IU, Bingman WE 3rd, Nakka M, Li W, Wang Q, Liu XS, Brown M, Weigel NL (2008) Target gene-specific regulation of androgen receptor activity by p42/p44 mitogen-activated protein kinase. Mol Endocrinol 22:2420–2432

    Article  PubMed  CAS  Google Scholar 

  50. Carey AM, Pramanik R, Nicholson LJ, Dew TK, Martin FL, Muir GH, Morris JD (2007) Ras-MEK-ERK signaling cascade regulates androgen receptor element-inducible gene transcription and DNA synthesis in prostate cancer cells. Int J Cancer 121:520–527

    Article  PubMed  CAS  Google Scholar 

  51. Gregory CW, Fei X, Ponguta LA, He B, Bill HM, French FS, Wilson EM (2004) Epidermal growth factor increases coactivation of the androgen receptor in recurrent prostate cancer. J Biol Chem 279:7119–7130

    Article  PubMed  CAS  Google Scholar 

  52. Font de Mora J, Brown M (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20:5041–5047

    Article  PubMed  CAS  Google Scholar 

  53. Rowan BG, Weigel NL, O’Malley BW (2000) Phosphorylation of steroid receptor coactivator-1. Identification of the phosphorylation sites and phosphorylation through the mitogen-activated protein kinase pathway. J Biol Chem 275:4475–4483

    Article  PubMed  CAS  Google Scholar 

  54. Wu RC, Qin J, Yi P, Wong J, Tsai SY, Tsai MJ, O’Malley BW (2004) Selective phosphorylations of the SRC-3/AIB1 coactivator integrate genomic reponses to multiple cellular signaling pathways. Mol Cell 15:937–949

    Article  PubMed  CAS  Google Scholar 

  55. Sen A, O’Malley K, Wang Z, Raj GV, Defranco DB, Hammes SR (2010) Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells. J Biol Chem 285:28787–28795

    Article  PubMed  CAS  Google Scholar 

  56. Sen A, De Castro I, Defranco DB, Deng FM, Melamed J, Kapur P, Raj GV, Rossi R, Hammes SR (2012) Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. J Clin Invest 122(7):2469–2481

    Article  PubMed  CAS  Google Scholar 

  57. Chng KR, Chang CW, Tan SK, Yang C, Hong SZ, Sng NY, Cheung E (2012) A transcriptional repressor co-regulatory network governing androgen response in prostate cancers. EMBO J 31:2810–2823

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Irina U. Agoulnik & Nancy L. Weigel

  2. Molecular Biology and Pharmacology, FIU College of Medicine, Miami, FL, USA

    Irina U. Agoulnik

Authors
  1. Irina U. Agoulnik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nancy L. Weigel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy L. Weigel .

Editor information

Editors and Affiliations

  1. , Shadyside Medical Center, University of Pittsburgh, Centre Ave 5200, Pittsburgh, 15232, Pennsylvania, USA

    Zhou Wang

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Agoulnik, I.U., Weigel, N.L. (2013). Roles of Androgen Receptor Coregulators and Cell Signaling in the Regulation of Androgen-Responsive Genes. In: Wang, Z. (eds) Androgen-Responsive Genes in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6182-1_1

Download citation

Publish with us

Policies and ethics

Search

Navigation