Mechanosensors Collaborate to Regulate DNA Damage Repair in Hepatocellular Carcinoma

Abstract Increased matrix stiffness is a biomechanical feature of hepatocellular carcinoma (HCC) that functions as an important promoting factor driving tumor progression. Characterization of the mechanosensors and the underlying downstream mechanisms driving HCC could help identify potential treatment strategies. In this study, we developed a standard procedure for screening and identifying mechanosensors, revealing two HCC mechanosensors, SDC4 and PKD2. These two mechanosensory pathways collaboratively mediated matrix stiffness–promoted DNA damage repair (DDR). Specifically, SDC4 and PKD2 modulated matrix stiffness–increased BANF1 nuclear translocation by increasing protein phosphatase 2A assembly and activity. Subsequently, nuclear BANF1 boosted the formation of the MRE11–RAD50–NBS1 complex and phosphorylation of its downstream effectors to enhance DDR. These findings not only expand the theoretical understanding of matrix stiffness–regulated DDR but also offer a screening/identification approach for mechanosensors in cancer. Significance: Matrix stiffness enhances DNA repair via dual pathways in hepatocellular carcinoma, suggesting that targeting mechanosensory crosstalk could be a potential strategy to overcome cytotoxic drug resistance.