Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2.
Scaffold attachment factor B1 regulates the androgen receptor in concert with the growth inhibitory kinase MST1 and the methyltransferase EZH2.
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雄激素受体（AR）是一种转录因子，在正常生理和前列腺癌（PCa）中与辅调节蛋白发生多种相互作用。AR介导与染色质复合物和激酶级联相关的细胞应答。在这里，我们报告说，核基质蛋白，支架附着因子B1（SAFB 1），调节AR活性和AR水平的方式，表明其参与PCa。在大多数公开可用的RNA表达数据集中，与正常前列腺组织相比，PCa中SAFB 1 mRNA表达较低。在包括转移性肿瘤的人PCa队列中，SAFB 1蛋白水平也随着疾病进展而降低。SAFB 1结合到AR上，并被MST 1（Hippo同源物）丝氨酸-苏氨酸激酶磷酸化，MST 1以前被证明是AR阻遏物，并且MST 1定位到AR依赖性启动子被SAFB 1耗尽抑制。雄激素依赖性LNCaP PCa细胞中SAFB 1的敲低增加了AR和前列腺特异性抗原（PSA）水平，刺激了培养细胞和皮下异种移植物的生长，并促进了更具侵略性的表型，与抑制性AR调节功能一致。SAFB 1与组蛋白甲基转移酶EZH 2在AR相互作用的染色质位点与其他多梳抑制复合物2（PRC 2）蛋白形成复合物。我们得出的结论是，SAFB 1在MST 1/Hippo和EZH 2途径信号会聚的基因位点上充当新型AR共调节因子。
The androgen receptor (AR) is a transcription factor that employs many diverse interactions with coregulatory proteins in normal physiology and in prostate cancer (PCa). The AR mediates cellular responses in association with chromatin complexes and kinase cascades. Here we report that the nuclear matrix protein, scaffold attachment factor B1 (SAFB1), regulates AR activity and AR levels in a manner that suggests its involvement in PCa. SAFB1 mRNA expression was lower in PCa in comparison with normal prostate tissue in a majority of publicly available RNA expression data sets. SAFB1 protein levels were also reduced with disease progression in a cohort of human PCa that included metastatic tumors. SAFB1 bound to AR and was phosphorylated by the MST1 (Hippo homolog) serine-threonine kinase, previously shown to be an AR repressor, and MST1 localization to AR-dependent promoters was inhibited by SAFB1 depletion. Knockdown of SAFB1 in androgen-dependent LNCaP PCa cells increased AR and prostate-specific antigen (PSA) levels, stimulated growth of cultured cells and subcutaneous xenografts and promoted a more aggressive phenotype, consistent with a repressive AR regulatory function. SAFB1 formed a complex with the histone methyltransferase EZH2 at AR-interacting chromatin sites in association with other polycomb repressive complex 2 (PRC2) proteins. We conclude that SAFB1 acts as a novel AR co-regulator at gene loci where signals from the MST1/Hippo and EZH2 pathways converge.
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