Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype.
Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype.
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去势抵抗性前列腺癌（CRPC）继续构成重大的临床挑战，新一代二线激素疗法对疾病结果的改善有限。由于雄激素受体 (AR) 仍然是 CRPC 的关键驱动因素，因此了解其转录活性的决定因素对于开发新的 AR 靶向疗法非常重要。 FOXA1 是 AR 转录复合物的关键组成部分，但其在前列腺癌进展中的作用以及 AR 和 FOXA1 之间的关系尚未完全解决。众所周知，FOXA1 水平在晚期前列腺癌和转移瘤中升高。我们通过在雄激素响应性 LNCaP 前列腺癌细胞系中过表达 FOXA1 来模拟这些条件，并观察到在染色质可及性增加的新区域中 AR 基因组结合显着增加。高水平的 FOXA1 会导致在次优浓度和高 5α-二氢睾酮 (DHT) 浓度下增殖增加。临床前列腺癌队列中 FOXA1 的免疫组织化学染色显示，FOXA1 高表达与根治性前列腺切除术后生化复发时间较短（HR 5.0，95% CI 1.2-21.1，p = 0.028）、手术切缘阳性和诊断时疾病分期较高相关。 FOXA1 过表达导致的基因表达程序富含 PTEN、Wnt 和 CRPC 基因特征中典型代表的其他途径。这些结果表明，在雄激素耗尽的状态下，FOXA1 水平升高会增强 AR 在通常不被 AR 占据的基因组区域的结合，从而促进前列腺癌细胞的生长。
Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by over-expressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (HR 5.0, 95% CI 1.2-21.1, p=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 over-expression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.
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