YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.
YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.
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DOI：
10.1038/ncomms9126
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发表时间：
2015-09-01
影响因子：
16.6
通讯作者：
Cinar B
中科院分区：
文献类型：
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作者：
Kuser-Abali G;Alptekin A;Lewis M;Garraway IP;Cinar B
转录共激活因子Yes相关蛋白1（YAP 1）是Hippo通路的关键核效应子，是一种有效的癌基因，然而，YAP 1与雄激素受体（AR）之间的相互作用尚未研究。在这里，我们确定YAP 1作为一个生理结合伴侣和积极的调节AR在前列腺癌。YAP 1和AR主要在细胞核内通过激素幼稚的雄激素依赖性机制和去势抵抗性前列腺癌细胞中的雄激素非依赖性机制共同定位和相互作用。生长抑制因子MST 1激酶通过直接调节YAP 1的核积累来调节雄激素依赖性和非依赖性的核YAP 1-AR相互作用。通过基因（RNAi）和药理学（Verteporfin）方法破坏YAP 1信号传导抑制AR依赖性基因表达和前列腺癌细胞生长。这些发现表明，YAP 1-AR轴可能在前列腺癌进展中起关键作用，并可作为可行的药物靶点。
The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Here we identify YAP1 as a physiological binding partner and positive regulator of AR in prostate cancer. YAP1 and AR co-localize and interact with each other predominantly within cell nuclei by an androgen-dependent mechanism in a hormone naive and an androgen-independent mechanism in castration-resistant prostate cancer cells. The growth suppressor MST1 kinase modulates androgen-dependent and -independent nuclear YAP1–AR interactions through directly regulating YAP1 nuclear accumulation. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1–AR axis may have a critical role in prostate cancer progression and serves as a viable drug target.