Neddylation E2 enzyme UBE2F promotes colitis and colon tumorigenesis by targeting the PTPRN-pSTAT5 axis

The inflammatory bowel diseases (IBDs) and colitis-associated colon cancers are common human diseases. Whether and how neddylation enzyme mechanistically regulates the process of these diseases are largely elusive. Here we report that UBE2F, a neddylation conjugation enzyme, plays a promoting role. UBE2F expression is significantly upregulated in IBDs, and mice with Ube2f deletion in colon epithelial cells are significantly more resistant to DSS-induced colitis and AOM-DSS induced colon tumorigenesis. Mechanistically, Ube2f deletion inactivates Cullin-RING ligase-5 (CRL5) E3, leading to accumulation of protein tyrosine phosphatase receptor type N (PTPRN), a new substrate of CRL5, and a stabilizer of p-STAT5, to promote differentiation of ISCs into secretory lineages for epithelial integrity against colitis, which is abrogated by a STAT5 PROTAC degrader. Ube2f deletion also reduces tumor incidence in the ApcMin/+ mouse model. An inverse correlation between UBE2F and PTPRN levels is found in human colon cancer tissues. Collectively, the UBE2F-CRL5-PTPRN-STAT5 axis plays a key role in colitis and colon tumorigenesis, and UBE2F serves as an attractive therapeutic target for IBD and colon cancer.