PDF(Pubmed)
Abstract：
SET domain containing 7(SETD7), a member of histone methyltransferases, is abnormally expressed in multiple tumor types. However, the biological function and underlying molecular mechanism of SETD7 in clear cell renal cell carcinoma (ccRCC) remain unclear. Here, we explored the biological effects of SETD7-TAF7-CCNA2 axis on proliferation and metastasis in ccRCC. We identified both SETD7 and TAF7 were up-regulated and significantly promoted the proliferation and migration of ccRCC cells. Concurrently, there was a significant positive correlation between the expression of SETD7 and TAF7, and the two were colocalized in the nucleus. Mechanistically, SETD7 methylates TAF7 at K5 and K300 sites, resulting in the deubiquitination and stabilization of TAF7. Furthermore, re-expression of TAF7 could partially restore SETD7 knockdown inhibited ccRCC cells proliferation and migration. In addition, TAF7 transcriptionally activated to drive the expression of cyclin A2 (CCNA2). And more importantly, the methylation of TAF7 at K5 and K300 sites exhibited higher transcriptional activity of CCNA2, which promotes formation and progression of ccRCC. Our findings reveal a unique mechanism that SETD7 mediated TAF7 methylation in regulating transcriptional activation of CCNA2 in ccRCC progression and provide a basis for developing effective therapeutic strategies by targeting members of SETD7-TAF7-CCNA2 axis.
摘要：
SET域包含7（SETD7），组蛋白甲基转移酶的成员，在多种肿瘤类型中异常表达。然而,SETD7在肾透明细胞癌（ccRCC）中的生物学功能和潜在的分子机制尚不清楚。这里,我们探讨了SETD7-TAF7-CCNA2轴对ccRCC增殖和转移的生物学效应。我们确定SETD7和TAF7均上调并显着促进ccRCC细胞的增殖和迁移。同时,SETD7和TAF7的表达呈显著正相关,二者在细胞核内共定位。机械上,SETD7在K5和K300位点甲基化TAF7，导致TAF7的去泛素化和稳定。此外，再表达TAF7可以部分恢复SETD7敲低抑制ccRCC细胞的增殖和迁移。此外,TAF7转录激活以驱动细胞周期蛋白A2(CCNA2)的表达。更重要的是,TAF7在K5和K300位点的甲基化表现出更高的CCNA2转录活性，促进ccRCC的形成和进展。我们的发现揭示了SETD7介导的TAF7甲基化在ccRCC进展中调节CCNA2转录激活的独特机制，并通过靶向SETD7-TAF7-CCNA2轴的成员为开发有效的治疗策略提供了基础。
