Mechanosensors Collaborate to Regulate DNA Damage Repair in Hepatocellular Carcinoma

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. Specifically, SDC4 and PKD2 modulated matrix stiffness-increased BANF1 nuclear translocation through increasing PP2A assembly and activity. Subsequently, nuclear BANF1 promoted the formation of MRN complex and phosphorylation of its downstream effectors to enhance DNA damage repair. These findings not only expand the theoretical understanding of matrix stiffness-regulated DNA damage repair but also offer a screening/identification approach for mechanosensors in cancer.