BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer. BRG1 knockdown inhibits proliferation through multiple cellular pathways in prostate cancer

Deregulation of the chromatin remodeller BRG1 contributes to a wide range of malignancies. In prostate cancer BRG1 is over expressed, however, the underlying function and cellular consequences of this are still being uncovered. Here, we have investigated the role of BRG1 in transcription regulation in prostate cancer. We found that BRG1 is over expressed in both the TCGA prostate cancer cohort as well as a panel of prostate cancer and transformed prostate cell lines. We then utilised a temporal model of BRG1 depletion followed by mRNA-seq to examine changes in gene expression. Surprisingly, we detected a modest overall effect, however, a number of genes associated with proliferation and cell cycle progression were down regulated. We find these genes were in part, co-regulated by AR and FOXA1. Corresponding cell cycle analysis conferred G1 arrest, and altered nuclei morphology with depletion of BRG1. This data provides mechanistic insight into the function of BRG1 in prostate cancer. Overall design: RNA-seq was conducted in LNCaP cells following SMARCA4/BRG1 knock-down.

染色质重塑因子BRG1（chromatin remodeller BRG1）的失调与多种恶性肿瘤的发生发展密切相关。在前列腺癌中，BRG1呈现过表达状态，但其具体功能及对应的细胞效应仍有待阐明。本研究针对BRG1在前列腺癌转录调控中的作用展开系统探究。我们在癌症基因组图谱（TCGA）前列腺癌队列及一组前列腺癌细胞系与转化前列腺细胞系中均检测到BRG1过表达。随后，我们构建了BRG1敲低的时序模型，并借助mRNA测序（mRNA-seq）分析基因表达变化。令人意外的是，整体基因表达仅出现较为温和的改变，但部分与细胞增殖及细胞周期进程相关的基因发生了下调。进一步分析显示，这些基因部分受到雄激素受体（Androgen Receptor, AR）与叉头框蛋白A1（Forkhead Box A1, FOXA1）的共同调控。对应的细胞周期实验结果表明，BRG1敲低会引发G1期阻滞，并伴随细胞核形态的异常改变。本研究数据为解析BRG1在前列腺癌中的功能提供了机制层面的深入见解。整体实验设计：在SMARCA4/BRG1敲低后的LNCaP细胞中开展RNA-seq测序实验。