Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China.
Cell Death Dis. 2021 Mar 4;12(3):239. doi: 10.1038/s41419-021-03521-1.
E3 ubiquitin ligase RNF126 (ring finger protein 126) is highly expressed in various cancers and strongly associated with tumorigenesis. However, its specific function in bladder cancer (BCa) is still debatable. Here, we found that RNF126 was significantly upregulated in BCa tissue by TCGA database, and our studies indicated that downregulation of RNF126 significantly inhibited cell proliferation and metastasis through the EGFR/PI3K/AKT signaling pathway in BCa cells. Furthermore, we identified PTEN, an inhibitor of the PI3K/AKT signaling pathway, as a novel substrate for RNF126. By co-immunoprecipitation assays, we proved that RNF126 directly interacts with PTEN. Predominantly, PTEN binds to the C-terminal containing the RING domain of RNF126. The in vivo ubiquitination assay showed that RNF126 specifically regulates PTEN stability through poly-ubiquitination. Furthermore, PTEN knockdown restored cell proliferation, metastasis, and tumor formation of BCa cells inhibited by RNF126 silencing in vitro and in vivo. In conclusion, these results identified RNF126 as an oncogene that functions through ubiquitination and degradation of PTEN in BCa.
E3 泛素连接酶 RNF126（环指蛋白 126）在各种癌症中高度表达，与肿瘤发生强烈相关。然而，其在膀胱癌（BCa）中的具体功能仍存在争议。在这里，我们通过 TCGA 数据库发现 RNF126 在 BCa 组织中显著上调，我们的研究表明，通过 EGFR/PI3K/AKT 信号通路下调 RNF126 可显著抑制 BCa 细胞的增殖和转移。此外，我们确定了 PTEN，PI3K/AKT 信号通路的抑制剂，是 RNF126 的一个新底物。通过共免疫沉淀实验，我们证明 RNF126 与 PTEN 直接相互作用。主要是，PTEN 与 RNF126 的 C 端环指结构域结合。体内泛素化实验表明，RNF126 通过多泛素化特异性调节 PTEN 的稳定性。此外，PTEN 敲低恢复了 RNF126 沉默体外和体内抑制的 BCa 细胞的增殖、转移和肿瘤形成。总之，这些结果表明 RNF126 通过泛素化和降解 PTEN 在 BCa 中发挥致癌作用。
