GTPBP4 enhances colorectal cancer cell proliferation by activating MYC-driven glycolysis

Background Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic targets. GTPBP4, a GTP-binding protein involved in ribosome biogenesis, has been implicated in several cancers, but its role and mechanism in CRC remain unclear. Methods Transcriptomic and clinical data from the TCGA and GEO databases were analyzed to identify genes that are differentially expressed in CRC. GTPBP4 expression was validated in CRC tissues and cell lines via immunohistochemistry, Western blotting, and qRT‒PCR. Functional assays, including CCK-8, EdU, and colony formation assays, were performed to assess cell proliferation. Ubiquitination assays and cycloheximide chase experiments were used to evaluate MYC protein stability. Glycolytic metabolites were measured via commercial assay kits. Results GTPBP4 was significantly overexpressed in CRC tissues and associated with poor patient survival. Knockdown of GTPBP4 inhibited CRC cell proliferation. GTPBP4 expression was positively correlated with MYC, and GTPBP4 depletion reduced MYC protein levels by increasing its ubiquitination and shortening its half-life. Furthermore, GTPBP4 knockdown downregulated key glycolytic enzymes (LDHA, PFKP, HK1) and decreased lactate, pyruvate, and glucose uptake, all of which were partially rescued by MYC overexpression. Conclusion GTPBP4 promotes colorectal cancer cell proliferation by stabilizing the MYC protein and enhancing MYC-driven glycolysis. These findings identify GTPBP4 as a potential biomarker and therapeutic target in CRC.