UHRF1 Drives Hepatocellular Carcinoma Progression via Epigenetic Repression of SFMBT2

Background Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, necessitating the identification of novel therapeutic targets. UHRF1 is an epigenetic regulator implicated in various cancers, but its precise mechanistic role in HCC progression remains incompletely understood. This study investigates the epigenetic mechanisms by which UHRF1 promotes HCC pathogenesis, with a focus on its interaction with SFMBT2. Methods A multifaceted approach integrating clinical sample analysis, bioinformatics, in vitro cell culture experiments, and in vivo xenograft models was employed. UHRF1 expression was assessed in HCC tissues and cell lines. Functional roles were investigated through overexpression and knockdown models, evaluated by MTT, Transwell, and Western blot assays. ChIP and luciferase reporter assays were used to examine promoter binding and transcriptional regulation. Results UHRF1 was significantly upregulated in HCC tissues and correlated with advanced tumor grade and poor survival. UHRF1 promoted HCC cell proliferation, migration, and invasion by activating the ERK/AKT/NF-κB signaling pathways. Mechanistically, UHRF1 bound to CpG islands in the SFMBT2 promoter, epigenetically repressing its expression. SFMBT2 overexpression reversed UHRF1-driven oncogenic effects in vitro and in vivo. Furthermore, UHRF1-mediated SFMBT2 downregulation led to increased HOXB13 expression, which transcriptionally activated LTK. Conclusions This study identifies a novel UHRF1/SFMBT2 epigenetic axis critical for HCC progression. UHRF1 represses SFMBT2 to activate ERK/AKT/NF-κB and HOXB13/LTK pathways, driving tumor aggressiveness. Restoration of SFMBT2 counteracts these effects, highlighting its tumor-suppressive role. These findings position UHRF1 as a promising prognostic biomarker and therapeutic target in HCC.