USP11 promotes lipogenesis and tumorigenesis by regulating SREBF1 stability in hepatocellular carcinoma

作者：Yongkang Xu, Jiayu Zeng, Kan Liu, Dan Li, Shenglan Huang, Shumin Fu, Mao Ye, Si Tao, Jianbing Wu · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01926-x · 被引用次数：13 · 研究领域：Ubiquitin and proteasome pathways、14-3-3 protein interactions、Ferroptosis and cancer prognosis

BACKGROUND: The relationship between hepatocellular carcinoma (HCC) metastasis and cancer metabolism reprogramming is becoming increasingly evident. Ubiquitin-specific protease 11 (USP11), a member of the deubiquitinating enzyme family, has been linked to various cancer-related processes. While USP11 is known to promote HCC metastasis and proliferation, the precise mechanisms, especially those related to cancer metabolism, remain unclear. METHODS: Through mass spectrometry, co-immunoprecipitation, immunofluorescence, and ubiquitination assays, we identified USP11 as the key deubiquitinase for SREBF1.Lipogenesis was evaluated using Oil Red O and Nile Red staining, along with the detection of triglycerides and cholesterol. To assess HCC cell proliferation, migration, and invasion in vitro, Transwell assays, EDU, colony formation, and CCK-8 were conducted. Xenograft models in nude mice were developed to verify the role of the USP11/SREBF1 axis in lipogenesis and tumor growth in vivo. RESULTS: USP11 directly interacts with SREBF1, and its silencing leads to the disruption of SREBF1 stabilization through K48-linked deubiquitination and degradation. Importantly, the truncated mutant USP11 (503-938 aa) interacts with the truncated mutant SREBF1 (569-1147aa), with K1151 playing a crucial role in this interaction. Higher levels of USP11 enhance lipogenesis, proliferation, and metastasis in HCC cells. Importantly, the knockdown of SREBF1 weakened the effects of USP11 in enhancing lipog...