FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.
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.
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Dominic
D
Jones
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Mark
M
Wade
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Sirintra
S
Nakjang
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Lewis
L
Chaytor
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
James
J
Grey
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Craig N
CN
Robson
Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK.
Luke
L
Gaughan
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds / Q000494:pharmacology
D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D001549:Benzamides; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide; C000595667:KLK2 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
FOXA1; androgen receptor variants; prostate cancer; transcriptional regulation