Abstract
BACKGROUND: The Rho GTPase-activating protein (RhoGAP) family represents a large and diverse group of proteins that act as key regulators of Rho GTPases, small GTP-binding proteins involved in cellular signaling. Tight regulation of Rho GTPase activity is essential for fundamental biological processes, including cell motility, contractility, growth, differentiation, and development. Despite their biological importance, the roles of RhoGAPs in cancer remain largely undefined. METHODS: Bioinformatics analysis was performed using data from The Cancer Genome Atlas (TCGA), covering over 10,000 samples across 33 cancer types. The role of ARHGAP11A in the DNA damage response was evaluated through single-cell sequencing, western blotting, and colony formation assays. RESULTS: Pan-cancer analysis of RhoGAP family genes identified ARHGAP11A as the most significantly overexpressed member in tumors compared to adjacent normal tissues. ARHGAP11A expression was found to be elevated in most cancer types and was associated with DNA repair activity. Furthermore, its expression positively correlated with tumor mutational burden (TMB), a recognized predictive biomarker for immunotherapy. Intriguingly, it also correlated with increased infiltration of regulatory T (Treg) cells, which are known to suppress anti-tumor immunity. Consistent with these observations, high ARHGAP11A expression was concurrently linked to poor patient survival outcomes across multiple cancers. We also observed a positive correlation between ARHGAP11A and CHK1, suggesting a functional collaboration. In vitro experiments further demonstrated that ARHGAP11A confers resistance to DNA damage induced by CHK1 inhibitors. CONCLUSION: ARHGAP11A is a promising prognostic marker in cancer, with potential therapeutic implications through targeting DNA repair pathways and modulating the tumor immune microenvironment.