Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7

Oncogene volume 37, pages 1326–1339 (2018)Cite this article

Subjects

Abstract

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Shafi AA, Yen AE, Weigel NL. Androgen receptors in hormone-dependent and castration-resistant prostate cancer. Pharmacol Ther 2013;140:223–38.

    Article  CAS  Google Scholar 

  2. Lu J, Van der Steen T, Tindall DJ, Are androgen receptor variants a substitute for the full-length receptor?. Nat Rev Urol. 2015;12:137–44.

    Article  CAS  Google Scholar 

  3. Imamura Y, Sadar MD. Androgen receptor targeted therapies in castration-resistant prostate cancer: bench to clinic. Int J Urol 2016;23:654–65.

    Article  Google Scholar 

  4. van de Wijngaart DJ, Dubbink HJ, van Royen ME, Trapman J, Jenster G. Androgen receptor coregulators: recruitment via the coactivator binding groove. Mol Cell Endocrinol 2012;352:57–69.

    Article  Google Scholar 

  5. Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting. Prostate Cancer Prostatic Dis 2016;19:231–41.

    Article  CAS  Google Scholar 

  6. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–38.

    Article  Google Scholar 

  7. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 2013;73:483–9.

    Article  CAS  Google Scholar 

  8. 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;16:1414–20.

    Article  CAS  Google Scholar 

  9. Jennbacken K, Tesan T, Wang W, Gustavsson H, Damber JE, Welen K. N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. Endocr Relat Cancer 2010;17:469–79.

    Article  CAS  Google Scholar 

  10. Cottard F, Asmane I, Erdmann E, Bergerat JP, Kurtz JE, Ceraline J. Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. PloS One 2013;8:e63466.

    Article  CAS  Google Scholar 

  11. Lu J, Lonergan PE, Nacusi LP, Wang L, Schmidt LJ, Sun Z, et al. The cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cells. J Urol 2015;193:690–8.

    Article  CAS  Google Scholar 

  12. Yu EJ, Kim SH, Heo K, Ou CY, Stallcup MR, Kim JH. Reciprocal roles of DBC1 and SIRT1 in regulating estrogen receptor a activity and co-activator synergy. Nucleic Acids Res 2011;39:6932–43.

    Article  CAS  Google Scholar 

  13. Chini CC, Escande C, Nin V, Chini EN. HDAC3 is negatively regulated by the nuclear protein DBC1. J Biol Chem 2010;285:40830–7.

    Article  CAS  Google Scholar 

  14. Li Z, Chen L, Kabra N, Wang C, Fang J, Chen J. Inhibition of SUV39H1 methyltransferase activity by DBC1. J Biol Chem 2009;284:10361–6.

    Article  CAS  Google Scholar 

  15. Qin B, Minter-Dykhouse K, Yu J, Zhang J, Liu T, Zhang H, et al. DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep 2015;10:1324–34.

    Article  CAS  Google Scholar 

  16. Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 2008;451:583–6.

    Article  CAS  Google Scholar 

  17. Kim HJ, Kim SH, Yu EJ, Seo WY, Kim JH. A positive role of DBC1 in PEA3-mediated progression of estrogen receptor-negative breast cancer. Oncogene 2015;34:4500–8.

    Article  CAS  Google Scholar 

  18. Yu EJ, Kim SH, Kim HJ, Heo K, Ou CY, Stallcup MR, et al. Positive regulation of beta-catenin-PROX1 signaling axis by DBC1 in colon cancer progression. Oncogene 2016;35:3410–8.

    Article  CAS  Google Scholar 

  19. Fu J, Jiang J, Li J, Wang S, Shi G, Feng Q, et al. Deleted in breast cancer 1, a novel androgen receptor (AR) coactivator that promotes AR DNA-binding activity. J Biol Chem 2009;284:6832–40.

    Article  CAS  Google Scholar 

  20. Seo WY, Jeong BC, Yu EJ, Kim HJ, Kim SH, Lim JE, et al. CCAR1 promotes chromatin loading of androgen receptor (AR) transcription complex by stabilizing the association between AR and GATA2. Nucleic Acids Res 2013;41:8526–36.

    Article  CAS  Google Scholar 

  21. Krause WC, Shafi AA, Nakka M, Weigel NL. Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol 2014;54:49–59.

    Article  CAS  Google Scholar 

  22. Kong D, Sethi S, Li Y, Chen W, Sakr WA, Heath E, et al. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of EMT and expression of stem cell marker genes. Prostate 2015;75:161–74.

    Article  CAS  Google Scholar 

  23. Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res 2012;72:3457–62.

    Article  CAS  Google Scholar 

  24. Takayama K, Kaneshiro K, Tsutsumi S, Horie-Inoue K, Ikeda K, Urano T, et al. Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis. Oncogene 2007;26:4453–63.

    Article  CAS  Google Scholar 

  25. Masuda K, Werner T, Maheshwari S, Frisch M, Oh S, Petrovics G, et al. Androgen receptor binding sites identified by a GREF_GATA model. J Mol Biol 2005;353:763–71.

    Article  CAS  Google Scholar 

  26. Makkonen H, Kauhanen M, Paakinaho V, Jaaskelainen T, Palvimo JJ. Long-range activation of FKBP51 transcription by the androgen receptor via distal intronic enhancers. Nucleic Acids Res 2009;37:4135–48.

    Article  CAS  Google Scholar 

  27. van der Steen T, Tindall DJ, Huang H. Posttranslational modification of the androgen receptor in prostate cancer. Int J Mol Sci 2013;14:14833–59.

    Article  Google Scholar 

  28. Lin HK, Wang L, Hu YC, Altuwaijri S, Chang C. Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase. EMBO J 2002;21:4037–48.

    Article  CAS  Google Scholar 

  29. Cardozo CP, Michaud C, Ost MC, Fliss AE, Yang E, Patterson C, et al. C-terminal Hsp-interacting protein slows androgen receptor synthesis and reduces its rate of degradation. Arch Biochem Biophys 2003;410:134–40.

    Article  CAS  Google Scholar 

  30. An J, Wang C, Deng Y, Yu L, Huang H. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep 2014;6:657–69.

    Article  CAS  Google Scholar 

  31. McClurg UL, Cork DMW, Darby S, Ryan-Munden CA, Nakjang S, Mendes Cortes L, et al. Identification of a novel K311 ubiquitination site critical for androgen receptor transcriptional activity. Nucleic Acids Res 2017;45:1793–804.

    Article  CAS  Google Scholar 

  32. Portillo-Lara R, Alvarez MM. Enrichment of the cancer stem phenotype in sphere cultures of prostate cancer cell lines occurs through activation of developmental pathways mediated by the transcriptional regulator DeltaNp63alpha. PloS One 2015;10:e0130118.

    Article  Google Scholar 

  33. Wagle S, Park SH, Kim KM, Moon YJ, Bae JS, Kwon KS, et al. DBC1/CCAR2 is involved in the stabilization of androgen receptor and the progression of osteosarcoma. Sci Rep 2015;5:13144.

    Article  CAS  Google Scholar 

  34. Noh SJ, Kang MJ, Kim KM, Bae JS, Park HS, Moon WS, et al. Acetylation status of P53 and the expression of DBC1, SIRT1, and androgen receptor are associated with survival in clear cell renal cell carcinoma patients. Pathology 2013;45:574–80.

    Article  CAS  Google Scholar 

  35. Park HS, Bae JS, Noh SJ, Kim KM, Lee H, Moon WS, et al. Expression of DBC1 and androgen receptor predict poor prognosis in diffuse large B cell lymphoma. Transl Oncol 2013;6:370–81.

    Article  Google Scholar 

  36. McGrath MJ, Binge LC, Sriratana A, Wang H, Robinson PA, Pook D, et al. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer Res 2013;73:5066–79.

    Article  CAS  Google Scholar 

  37. Liu G, Sprenger C, Wu PJ, Sun S, Uo T, Haugk K, et al. MED1 mediates androgen receptor splice variant induced gene expression in the absence of ligand. Oncotarget 2015;6:288–304.

    CAS  PubMed  Google Scholar 

  38. Fu M, Wang C, Wang J, Zhang X, Sakamaki T, Yeung YG, et al. Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol Cell Biol 2002;22:3373–88.

    Article  CAS  Google Scholar 

  39. Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, et al. Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol 2006;26:8122–35.

    Article  CAS  Google Scholar 

  40. DePaolo JS, Wang Z, Guo J, Zhang G, Qian C, Zhang H, et al. Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis. Oncotarget 2016;7:71417–28.

    Article  Google Scholar 

  41. 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;72:527–36.

    Article  CAS  Google Scholar 

  42. Beltran H, Yelensky R, Frampton GM, Park K, Downing SR, MacDonald TY, et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur Urol 2013;63:920–6.

    Article  CAS  Google Scholar 

  43. van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL, et al. Molecular characterization of human prostate carcinoma cell lines. Prostate 2003;57:205–25.

    Article  Google Scholar 

  44. Cronauer MV, Schulz WA, Burchardt T, Ackermann R, Burchardt M. Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines. Oncogene 2004;23:3541–9.

    Article  CAS  Google Scholar 

  45. Kim JH, Yang CK, Heo K, Roeder RG, An W, Stallcup MR. CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes. Mol Cell 2008;31:510–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. Robert Roeder (Rockefeller University) for HA-Ubiquitin expression plasmid. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning [2016R1A2B4008661]; and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea [HI17C0117].

Author information

Authors and Affiliations

  1. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Korea

    Sue Jin Moon, Hwa Jin Kim & Jeong Hoon Kim

  2. Department of Biomedical Sciences, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

    Sue Jin Moon, Hwa Jin Kim & Jeong Hoon Kim

  3. Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Byong Chang Jeong & Joung Eun Lim

  4. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Ghee Young Kwon

Authors
  1. Sue Jin Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byong Chang Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hwa Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joung Eun Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ghee Young Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeong Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeong Hoon Kim.

Ethics declarations

Conflict of interests

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moon, S.J., Jeong, B.C., Kim, H.J. et al. DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7. Oncogene 37, 1326–1339 (2018). https://doi.org/10.1038/s41388-017-0047-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-017-0047-5

This article is cited by

Search

Advanced search

Quick links