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BACKGROUND: HEG1 (Heart of Glass 1) is an endothelial cell-associated protein with emerging roles in oncogenesis, though its function in gastric cancer (GC) remains poorly understood. This study investigates the role of HEG1 in GC progression and uncovers the regulatory mechanism involving the deubiquitinase USP48. METHODS: Comprehensive bioinformatics analyses, in vitro and in vivo assays, were employed to evaluate the expression, function, and mechanistic regulation of HEG1 in GC. RNA-seq, protein interaction studies, immunoprecipitation assays, and pharmacogenomic data analysis were used to explore the HEG1-AKT1 axis and its modulation by USP48. RESULTS: HEG1 was significantly overexpressed in GC tissues and cell lines, and high HEG1 expression correlated with advanced tumor grade, TP53 wild-type status, and poor prognosis. Functional studies revealed that HEG1 promotes GC cell proliferation, clonogenicity, and tumor growth in vivo. Mechanistically, HEG1 stabilizes AKT1 by reducing its ubiquitination, leading to sustained activation of the AKT signaling pathway. Importantly, USP48 was identified as a novel deubiquitinase of HEG1. USP48 directly interacts with and stabilizes HEG1 by removing K48-linked polyubiquitin chains, thereby preventing proteasomal degradation. CONCLUSION: HEG1 acts as a key oncogenic regulator in gastric cancer by modulating AKT1 stability and cell proliferative potential. Its stability is critically dependent on USP48-mediated deubiquitination. The USP48-HEG1-AKT1 axis represents a novel regulatory pathway in gastric cancer progression and a potential target for therapeutic intervention.
Zhao et al. (Fri,) studied this question.