FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer

Jones, Dominic; Wade, Mark; Nakjang, Sirintra; Chaytor, Lewis; Grey, James; Robson, Craig N.; Gaughan, Luke

Abstract

Retention of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the requirement for the development of more effective AR targeting therapies. A key mechanism of resistance to anti-androgens is through expression of constitutively active AR variants (AR-Vs) that are refractory to next-generation therapies, including Enzalutamide and Abiraterone. By maintaining an androgenic gene signature, AR-Vs drive tumour survival and progression in castrate conditions. Critically, however, our understanding of the mechanics of AR-V-driven transcription is limited, particularly with respect to dependency on pioneer factor function. Here we show that depletion of FOXA1 in the CWR22Rv1 CRPC cell line abrogates the oncogenic potential of AR-Vs. Gene expression profiling reveals that approximately 41% of the AR-V transcriptome requires FOXA1 and that depletion of FOXA1 attenuates AR-V binding at a sub-set of analysed co-regulated genes. Interestingly, AR-V levels are elevated in cells depleted of FOXA1 as a consequence of attenuated negative feedback on the AR gene, but is insufficient to maintain cell growth as evidenced by marked anti-proliferative effects in FOXA1 knockdown cells. In all, our data suggests that AR-Vs are dependent on FOXA1 for sustaining a pro-proliferative gene signature and agents targeting FOXA1 may represent novel therapeutic options for CRPC patients.

Citation

Jones, D., Wade, M., Nakjang, S., Chaytor, L., Grey, J., Robson, C. N., & Gaughan, L. (2015). FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer. Oncotarget, 6(30), 29782-29794. https://doi.org/10.18632/oncotarget.4927

• Journal Article Type: Article
• Acceptance Date: Aug 3, 2015
• Online Publication Date: Aug 14, 2015
• Publication Date: Oct 6, 2015
• Deposit Date: Feb 4, 2019
• Publicly Available Date: Feb 5, 2019
• Journal: Oncotarget
• Print ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 30
• Pages: 29782-29794
• DOI: https://doi.org/10.18632/oncotarget.4927
• Keywords: Prostate cancer; Androgen receptor variants; FOXA1; Transcriptional regulation
• Public URL: https://hull-repository.worktribe.com/output/1271249
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=4927&path[]=13002
• Contract Date: Feb 4, 2019