Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal-Epithelial Transition in Kidney Tumor Cells
Loss of BAP1 Results in Growth Inhibition and Enhances Mesenchymal-Epithelial Transition in Kidney Tumor Cells
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BAP1 缺失会导致肾肿瘤细胞生长抑制并增强间质-上皮转化
DOI：
10.1074/mcp.ra119.001457
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发表时间：
2019-07-01
影响因子：
7
通讯作者：
Deng, Haiteng
中科院分区：
文献类型：
--
作者：
Chen, Pengsheng;Wang, Huan;Deng, Haiteng
BRCA 1相关蛋白1（BAP 1）是去泛素化酶的泛素C-末端水解酶家族的成员，并参与转录调控。BAP 1基因在约10%的ccRCC患者中发生突变，这是最常见的肾癌形式，表明BAP 1是一种肿瘤抑制因子。然而，BAP 1是否影响表达野生型（WT）BAP 1的ccRCC肿瘤的进展尚不清楚。在这里，我们使用人ccRCC标本和细胞系评估了BAP 1的表达和功能。对癌症基因组图谱中数据集的分析显示，较低的BAP 1表达与ccRCC患者较长的总生存期相关。我们建立了具有稳定BAP 1敲除的人ccRCC细胞系，并对BAP 1介导的细胞过程进行了多组学分析。BAP 1敲除下调与蛋白质合成相关的蛋白质，导致细胞生长减少。重要的是，BAP 1的缺失减少了应力纤维和膜突起的形成，并诱导了迁移和侵袭缺陷。在ccRCC细胞中敲除BAP 1还下调转录抑制蛋白Snail的表达，并降低Rho家族GTP酶的活性，促进细胞经历间质-上皮转化。出乎意料的是，定量蛋白质组学还表明，BAP 1敲除增加了几种氨基酸转运蛋白和多种酪氨酸激酶的表达，包括表皮生长因子受体。总的来说，我们的研究结果表明，BAP 1调节多个细胞过程，我们还发现了BAP 1在控制ccRCC细胞中的间充质-上皮转化中的新作用。
BRCA1-associated protein 1 (BAP1) is a member of the ubiquitin C-terminal hydrolase family of deubiquitinating enzymes and is implicated in transcriptional regulation. The BAP1 gene is mutated in about 10% of patients with ccRCC, the most common form of renal cancer, suggesting that BAP1 is a tumor suppressor. However, whether BAP1 influences the progression of ccRCC tumors expressing wild-type (WT) BAP1 is unclear. Here, we assessed the expression and function of BAP1 using human ccRCC specimens and cell lines. Analysis of datasets in The Cancer Genome Atlas revealed that lower BAP1 expression is correlated with longer overall survival of ccRCC patients. We established human ccRCC cell lines with stable BAP1 knockout and performed multiomic analysis of BAP1-mediated cellular processes. BAP1 knockout downregulated proteins associated with protein synthesis, resulting in decreased cell growth. Importantly, loss of BAP1 decreased the formation of stress fibers and membrane protrusions and induced migration and invasion defects. BAP1 knockout in ccRCC cells also downregulated the expression of transcriptional repressor protein Snail and decreased the activity of Rho family GTPases, promoting the cells to undergo mesenchymal-epithelial transition. Unexpectedly, quantitative proteomics also showed that BAP1 knockout increased expression of several amino acid transporters and multiple tyrosine kinases, including the epidermal growth factor receptor. Overall, our results suggest that BAP1 regulates multiple cellular processes, and we also uncover a new role for BAP1 in controlling mesenchymal-epithelial transition in ccRCC cells.