PBRM1 Regulates the Expression of Genes Involved in Metabolism and Cell Adhesion in Renal Clear Cell Carcinoma.
PBRM1 Regulates the Expression of Genes Involved in Metabolism and Cell Adhesion in Renal Clear Cell Carcinoma.
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DOI：
10.1371/journal.pone.0153718
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Dykhuizen EC
中科院分区：
文献类型：
--
作者：
Chowdhury B;Porter EG;Stewart JC;Ferreira CR;Schipma MJ;Dykhuizen EC
多溴-1（PBRM 1）是PBAF（多溴相关-BRG 1-或BRM相关因子）染色质重塑复合物的组分，是透明细胞肾细胞癌（ccRCC）中第二个最常见的突变基因。PBRM 1的突变被认为是癌症发生的早期事件，但其作为肿瘤抑制因子的功能尚不清楚。在这项研究中，我们采用下一代测序技术来分析ccRCC细胞模型中PBRM 1重新表达后差异表达的基因。PBRM 1重新表达导致参与细胞粘附、碳水化合物代谢、凋亡过程和对缺氧的反应的基因上调，以及参与细胞分裂不同阶段的基因下调。证实了PBRM 1再表达后细胞增殖的减少，验证了PBRM 1在基于细胞的模型中作为肿瘤抑制因子的功能作用。此外，我们确定了PBRM 1在调节已知对驱动ccRCC重要的代谢途径中的作用，包括调节缺氧反应基因、PI 3 K信号传导、葡萄糖摄取和胆固醇稳态。特别新奇的是鉴定细胞粘附作为由PBRM 1表达独特调控的主要下游过程。细胞骨架重组诱导PBRM 1的再表达，从显示皮质肌动蛋白，上皮细胞的标志的细胞数量的增加证明。参与细胞粘附的基因在我们的转录数据集中表现突出，并与ccRCC临床标本中PBRM 1独特调控的基因重叠。参与细胞粘附的基因是肿瘤抑制基因，可能参与抑制细胞迁移。在这里，我们首次报道了与细胞粘附相关的基因作为PBRM 1的下游靶点，并希望为未来研究染色质重塑在恶性肿瘤中引起这些改变的作用奠定基础。
Polybromo-1 (PBRM1) is a component of the PBAF (Polybromo-associated-BRG1- or BRM-associated factors) chromatin remodeling complex and is the second most frequently mutated gene in clear-cell renal cell Carcinoma (ccRCC). Mutation of PBRM1 is believed to be an early event in carcinogenesis, however its function as a tumor suppressor is not understood. In this study, we have employed Next Generation Sequencing to profile the differentially expressed genes upon PBRM1 re-expression in a cellular model of ccRCC. PBRM1 re-expression led to upregulation of genes involved in cellular adhesion, carbohydrate metabolism, apoptotic process and response to hypoxia, and a downregulation of genes involved in different stages of cell division. The decrease in cellular proliferation upon PBRM1 re-expression was confirmed, validating the functional role of PBRM1 as a tumor suppressor in a cell-based model. In addition, we identified a role for PBRM1 in regulating metabolic pathways known to be important for driving ccRCC, including the regulation of hypoxia response genes, PI3K signaling, glucose uptake, and cholesterol homeostasis. Of particular novelty is the identification of cell adhesion as a major downstream process uniquely regulated by PBRM1 expression. Cytoskeletal reorganization was induced upon PBRM1 reexpression as evidenced from the increase in the number of cells displaying cortical actin, a hallmark of epithelial cells. Genes involved in cell adhesion featured prominently in our transcriptional dataset and overlapped with genes uniquely regulated by PBRM1 in clinical specimens of ccRCC. Genes involved in cell adhesion serve as tumor suppressor and maybe involved in inhibiting cell migration. Here we report for the first time genes linked to cell adhesion serve as downstream targets of PBRM1, and hope to lay the foundation of future studies focusing on the role of chromatin remodelers in bringing about these alterations during malignancies.