Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.
Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer.
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DOI：
10.1158/0008-5472.can-16-1616
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发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
Selth LA
中科院分区：
文献类型：
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作者：
Paltoglou S;Das R;Townley SL;Hickey TE;Tarulli GA;Coutinho I;Fernandes R;Hanson AR;Denis I;Carroll JS;Dehm SM;Raj GV;Plymate SR;Tilley WD;Selth LA
前列腺癌中雄激素受体（AR）辅助调节因子的表达和活性改变是导致疾病进展和治疗耐药性的重要机制。使用一种新的蛋白质组学技术，我们确定了一个新的AR共调节因子，转录因子Grainyhead-like 2（GRHL 2），并证明了其在致癌AR信号转导轴中的重要作用。GRHL 2在前列腺肿瘤中与AR共定位，并且在前列腺癌中频繁扩增和上调。重要的是，GRHL 2在多种前列腺癌模型系统中维持AR表达，是细胞增殖所需的，增强AR的转录活性，并与AR共同定位在染色质上的特定位点以调节与疾病进展相关的基因。GRHL 2本身是一个AR调节基因，在两个因子之间形成了一个正反馈回路。GRHL 2和AR之间的联系也适用于组成型活性截短AR变体（ARV），因为GRHL 2与ARV相互作用并调节ARV，反之亦然。GRHL 2的这些致癌功能被其抑制上皮-间质转化和细胞侵袭的能力所抵消。机制证据表明，AR协助GRHL 2维持上皮表型。总之，这项研究已经确定了一种新的AR辅助调节因子，在前列腺癌中具有多方面的作用，作为致癌AR信号通路的增强子，但也是转移相关表型的抑制子。
Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs and vice versa. These oncogenic functions of GRHL2 were counterbalanced by its ability to suppress epithelial-mesenchymal transition and cell invasion. Mechanistic evidence suggested that AR assisted GRHL2 in maintaining the epithelial phenotype. In summary, this study has identified a new AR co-regulator with a multifaceted role in prostate cancer, functioning as an enhancer of the oncogenic AR signaling pathway but also a suppressor of metastasis-related phenotypes.