State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200240, China.
Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, 200030, China.
Cancer Lett. 2021 Oct 10;518:266-277. doi: 10.1016/j.canlet.2021.07.044. Epub 2021 Jul 30.
Dysregulated ubiquitination of tumor-related proteins plays a critical role in tumor development and progression. The deubiquitinase USP22 is aberrantly expressed in certain types of cancer and contributes to aggressive tumor progression. However, the precise mechanism underlying the pro-tumorigenic function of USP22 in hepatocellular carcinoma (HCC) remains unclear. Here, we report that E2F6, a pocket protein-independent transcription repressor, is essential for HCC cell growth, and that its activities are controlled by USP22-mediated deubiquitination. USP22 interacts with and stabilizes E2F6, resulting in the transcriptional repression of phosphatase DUSP1. Moreover, the process involving DUSP1 repression by E2F6 strengthens AKT activation in HCC cells. Therefore, these findings provide mechanistic insights into the USP22-mediated control of oncogenic AKT signaling, emphasizing the importance of USP22-E2F6 regulation in HCC development.
肿瘤相关蛋白的泛素化失调在肿瘤的发生和发展中起着关键作用。去泛素化酶 USP22 在某些类型的癌症中异常表达，促进了侵袭性肿瘤的进展。然而，USP22 在肝细胞癌 (HCC) 中的促肿瘤功能的确切机制尚不清楚。在这里，我们报告称，E2F6（一种与 pocket 蛋白无关的转录抑制因子）对 HCC 细胞的生长是必需的，其活性受到 USP22 介导的去泛素化的控制。USP22 与 E2F6 相互作用并稳定 E2F6，导致磷酸酶 DUSP1 的转录抑制。此外，E2F6 抑制 DUSP1 的过程增强了 HCC 细胞中 AKT 的激活。因此，这些发现为 USP22 介导的致癌 AKT 信号的控制提供了机制见解，强调了 USP22-E2F6 调控在 HCC 发生中的重要性。
