Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer
Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer
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DOI：
10.1038/emboj.2011.328
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发表时间：
2011-10-05
期刊：
影响因子：
11.4
通讯作者：
Janne, Olli A.
中科院分区：
文献类型：
--
作者：
Sahu, Biswajyoti;Laakso, Marko;Janne, Olli A.
原发肿瘤中高雄激素受体(AR)水平预示前列腺癌特异性死亡率增加。然而，前列腺癌中调节AR功能的机制却知之甚少。我们在这里报告了一个新的范例，叉头蛋白FoxA1在雄激素信号中的作用。除了开创AR途径，FoxA1缺失还引起LNCaP-1F5细胞染色质上AR结合位点(ARB)的广泛重新分布，这与雄激素依赖基因表达特征的变化相适应。我们鉴定了三类不同的ARB和雄激素反应基因：(I)独立于FoxA1，(Ii)由FoxA1开创，(Iii)被FoxA1掩盖，并在FoxA1耗尽时发挥功能。FOXA1的缺失还重新编程了VCaP细胞的AR结合，以及LNCaP-1F5细胞的糖皮质激素受体结合和糖皮质激素依赖的信号转导。重要的是，原发前列腺肿瘤中FoxA1蛋白水平与疾病预后显著相关；高水平FoxA1与预后不良相关，而低水平FoxA1，即使在AR高表达的情况下，也预示着良好预后。FoxA1在雄激素信号和前列腺癌中的作用与在雌激素信号和乳腺癌中的作用明显不同。EMBO期刊(2011)30,3962-3976。DOI：10.1038/Intemj.2011.328；2011年9月13日在线发布
High androgen receptor (AR) level in primary tumour predicts increased prostate cancer-specific mortality. However, the mechanisms that regulate AR function in prostate cancer are poorly known. We report here a new paradigm for the forkhead protein FoxA1 action in androgen signalling. Besides pioneering the AR pathway, FoxA1 depletion elicited extensive redistribution of AR-binding sites (ARBs) on LNCaP-1F5 cell chromatin that was commensurate with changes in androgen-dependent gene expression signature. We identified three distinct classes of ARBs and androgen-responsive genes: (i) independent of FoxA1, (ii) pioneered by FoxA1 and (iii) masked by FoxA1 and functional upon FoxA1 depletion. FoxA1 depletion also reprogrammed AR binding in VCaP cells, and glucocorticoid receptor binding and glucocorticoid-dependent signalling in LNCaP-1F5 cells. Importantly, FoxA1 protein level in primary prostate tumour had significant association to disease outcome; high FoxA1 level was associated with poor prognosis, whereas low FoxA1 level, even in the presence of high AR expression, predicted good prognosis. The role of FoxA1 in androgen signalling and prostate cancer is distinctly different from that in oestrogen signalling and breast cancer. The EMBO Journal (2011) 30, 3962-3976. doi:10.1038/emboj.2011.328; Published online 13 September 2011