Cmtm3 Promotes Colitis-Associated Carcinogenesis Via Exacerbating Colitis by Stablizing Cltc and Increasing Clathrin Mediated Ve-Cadherin Endocytosis

Inflammatory bowel disease leads to increased risk of developing colitis-associated colon cancer. CMTM3 has a higher methylation level in colon cancer, and accumulating evidence suggests that CMTM3 participates in inflammation and cancer development. But whether it plays a role in colitis initiation and colitis associated colon cancer (CAC) is unknown. Here, we explored the signs of azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CAC in wild-type (WT) and Cmtm3 deficiency (Cmtm3-/-) mice. Notably, we found CMTM3 promoted CAC by aggravating colitis. Further we revealed endothelial cell-specific deletion of Cmtm3 inhibited the colitis development. In vitro and in vivo mechanistic studies revealed that CMTM3 drived colitis by increasing clathrin-dependent endocytosis of vascular endothelial (VE)-cadherin, thus causing vascular permeability. We further identified that CMTM3 interacted with clathrin heavy chain (CLTC) and inhibited CLTC ubiquitination and proteasome-dependent degradation. Interestingly, Cmtm3 knockout and imatinib mesylate both targeted vascular permeability and had comparable efficacy. Our study indicates that CMTM3 promotes CAC by aggravating colitis through causing vascular permeability, providing insights into targets for development of future therapies.