FAIM modulates HCC progression via enhancing HMGA1 interaction with CDK7 and promoting its phosphorylation level.

BACKGROUND: Hepatocellular carcinoma (HCC), characterized by its aggressive trait and rapid progression, stands as one of the leading causes of cancer-related death worldwide. Fas apoptotic inhibitory molecule (FAIM), a death receptor antagonist, impedes cell apoptosis by reinforcing protein phosphorylation and stability. High mobility group A1 (HMGA1) is reported to be subject to multiple posttranslational modification, and plays a crucial role in HCC development. However, whether FAIM facilitates tumorigenesis through modulating HMGA1 phosphorylation remains unclear. METHODS: We applied Huh7 and SNU387 cells to investigate the regulatory role of FAIM in cell proliferation and apoptosis. Next, we constructed a male BALB/C mouse model with HCC to explore the biological function of FAIM in tumor growth. Subsequently, anti-FAIM proteomic and phosphorylation proteomic profiles were performed to screen HMGA1 as the FAIM-modulated downstream phosphorylated protein. Eventually, a series of immunoprecipitation (IP) tests and in vitro kinase assay revealed the crosstalk of FAIM, cyclin-dependent kinase7 (CDK7) and HMGA1, and unveiled the vital value of FAIM in HCC pathogenesis. RESULTS: In vitro and in vivo experiments validated that FAIM overexpression was advantageous for HCC progression. Thereafter, anti-FAIM proteomic profile identified that FAIM interacted with CDK7 and HMGA1. Phosphorylation proteomic profile revealed that the Ser36 of HMGA1 was a downstream phosphorylation site of FAIM. Consistently, Co-IP and cycloheximide assays verified that FAIM enhanced HMGA1 phosphorylation and stability. More importantly, recovery experiments identified that silencing HMGA1 altered the regulatory role of overexpressed FAIM in Huh7 cells. Furthermore, we transduced Flag-HMGA1(WT) or Flag-HMGA1(S36A) plasmids into overexpressed FAIM cells and demonstrated that Ser36 phosphorylation influenced HMGA1 stability. CONCLUSIONS: Summarily, we elucidated that FAIM modulated HCC progression through facilitating the interaction of CDK7 and HMGA1 as well as elevating HMGA1 phosphorylation and stability.