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

Oncotarget
Dominic JonesLuke Gaughan

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 suggest...Continue Reading

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Citations

Dec 7, 2016·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·Q LiB Qiao
Feb 24, 2018·The Prostate·Ben T CopelandJeremy O Jones
Feb 17, 2017·Scientific Reports·Dominic JonesLuke Gaughan
Oct 5, 2017·International Journal of Molecular Sciences·U-Ging LoJer-Tsong Hsieh
Dec 10, 2017·Journal of Cell Science·Victoria G ShuttleworthIan R Logan
Dec 15, 2016·Development·Maria L Golson, Klaus H Kaestner
Oct 27, 2018·International Journal of Molecular Sciences·Duc-Hiep BachSang Kook Lee
Feb 19, 2021·Clinical Epigenetics·Katherine A GilesPhillippa C Taberlay
Jul 3, 2021·International Journal of Molecular Sciences·Md Hafiz UddinElisabeth I Heath

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Methods Mentioned

BETA
immunoprecipitation
PCR
ChIP
flow cytometry
ChIP-Seq
transfection
FCS

Software Mentioned

GSEA
Excel
siAR DOWN
R package ‘ Lumi ’
R package ‘ Limma ’

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