FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.
FOXA1 regulates androgen receptor variant activity in models of castrate-resistant prostate cancer.
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DOI：
10.18632/oncotarget.4927
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发表时间：
2015-10-06
期刊：
影响因子：
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通讯作者：
Gaughan L
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文献类型：
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作者：
Jones D;Wade M;Nakjang S;Chaytor L;Grey J;Robson CN;Gaughan L
去势抵抗性前列腺癌（CRPC）中雄激素受体（AR）信号传导的保留突出了开发更有效的AR靶向治疗的需求。对抗雄激素药物耐药的一个关键机制是通过表达组成型活性AR变体（AR-V），这些变体对下一代治疗（包括Enzalutamide和阿比特龙）无效。通过维持雄激素基因特征，AR-Vs在去势条件下驱动肿瘤存活和进展。然而，至关重要的是，我们对AR-V驱动的转录机制的理解是有限的，特别是在对先锋因子功能的依赖性方面。在这里，我们表明，在CWR 22 Rv 1 CRPC细胞系中的FOXA 1的耗尽废除了AR-Vs的致癌潜力。基因表达谱显示，大约41%的AR-V转录组需要FOXA 1和FOXA 1的耗尽减弱AR-V结合在一个子集的分析共调节基因。有趣的是，由于AR基因上的负反馈减弱，AR-V水平在FOXA 1耗尽的细胞中升高，但不足以维持细胞生长，如FOXA 1敲减细胞中显著的抗增殖作用所证明的。总之，我们的数据表明，AR-V依赖于FOXA 1来维持促增殖基因特征，靶向FOXA 1的药物可能代表CRPC患者的新治疗选择。
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.