The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer.
The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer.
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DOI：
10.1158/0008-5472.can-08-1794
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发表时间：
2008-12-15
期刊：
影响因子：
11.2
通讯作者：
Knudsen KE
中科院分区：
文献类型：
--
作者：
Shen H;Powers N;Saini N;Comstock CE;Sharma A;Weaver K;Revelo MP;Gerald W;Williams E;Jessen WJ;Aronow BJ;Rosson G;Weissman B;Muchardt C;Yaniv M;Knudsen KE
推动前列腺癌进展的因素仍然定义不清，从而阻碍了新治疗策略的开发。由于前列腺癌细胞的生长和存活需要雄激素，因此通过消融雄激素信号传导的方案来治疗播散性肿瘤。然而，复发性，无法治愈的肿瘤，绕过雄激素的要求，最终出现。这项研究表明，Brm ATP酶，一个选定的SWI/SNF复合物的组成部分，具有显着的抗前列腺增生功能，防止这些转换。首先，我们表明，有针对性地消融Brm是导致小鼠前列腺增生的原因。其次，体内挑战表明Brm-/-上皮细胞获得了肺叶特异性、抗阉割细胞增殖的能力。第三，对人类样本的研究表明，Brm mRNA和蛋白质水平在前列腺癌中减弱。第四，Brm下调与增殖指数增加相关，与小鼠模型一致。最后，基因表达谱显示Brm缺失改变了E2 F1上游的因子;这在鼠模型中得到证实，其中Brm缺失以组织特异性方式诱导E2 F1失调。结合，这些数据确定Brm作为血清雄激素诱导的前列腺增殖的主要效应物，在人类疾病中被破坏，并表明Brm的损失赋予前列腺癌的增殖优势。
Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm−/− epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen–induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer.