FAM117B Promotes Malignant Progression of Hepatocellular Carcinoma by Forming a Bidirectional Regulatory Loop with NAT10 and Activating the JAK-STAT3 Pathway.

Abstract

HCC (Hepatocellular carcinoma) is one of the malignant tumors with high morbidity and mortality worldwide. Its pathogenesis is complex and the efficacy of existing treatments is limited. Therefore, in-depth exploration of key regulatory molecules and their mechanisms is of great significance for the early diagnosis and targeted therapy of HCC. In this study, HCC cell lines Huh-7 and HepG2 were used as research models to systematically investigate the biological function and molecular regulatory mechanism of FAM117B (family with sequence similarity 117 member B) in HCC progression through gene knockdown and overexpression, cell functional assays, co-immunoprecipitation coupled with mass spectrometry, post-translational modification detection, transcriptome sequencing and nude mouse subcutaneous tumorigenesis assays. High FAM117B expression predicted poor prognosis and positively correlated with pathological grade; functionally, FAM117B exhibited robust oncogenic activity, where its knockdown suppressed proliferation, clonogenicity, invasion, and migration, and its overexpression enhanced these phenotypes. Mechanistic studies revealed that FAM117B directly physically interacted with NAT10 (N-acetyltransferase 10), an acetyltransferase, forming a bidirectional regulatory loop: on the one hand, FAM117B maintained the protein stability of NAT10 by inhibiting its K48-linked ubiquitination and subsequent proteasomal degradation; on the other hand, NAT10, as a key acetyltransferase, specifically mediated the acetylation of FAM117B at lysine 429, providing a molecular basis for the functional role of FAM117B. Transcriptome sequencing and molecular verification demonstrated that the FAM117B/NAT10 axis targeted and regulated JAK2 (Janus kinase 2) expression, activated the downstream JAK-STAT3 (signal transducer and activator of transcription 3) signaling pathway, and thereby drove the malignant biological behaviors of HCC cells. In vivo, dual knockdown of FAM117B and NAT10 significantly reduced xenograft growth, decreased Ki67, and increased apoptosis; notably, NAT10 depletion abrogated the tumor-promoting effects of FAM117B overexpression. In conclusion, this study reveals the molecular mechanism by which FAM117B promotes HCC progression via forming a bidirectional regulatory loop with NAT10 and activating the JAK-STAT3 signaling pathway through acetylation modification, providing a novel potential target and theoretical basis for targeted therapy of HCC.