OTUD4 suppresses colorectal cancer progression through deubiquitinating p53

Colorectal cancer (CRC) represents a global health burden as the third most commonly diagnosed malignancy and the second leading cause of cancer-related mortality. Despite advances in research, molecular mechanisms driving CRC initiation, progression, and metastasis remain incompletely elucidated. OTU domain-containing protein 4 (OTUD4), a deubiquitinating enzyme of the ovarian tumor family, catalyzes ubiquitin chain removal from substrate proteins. While implicated in diverse cellular processes, OTUD4’s role in CRC pathogenesis is undefined. Here, we report significant downregulation of OTUD4 in CRC specimens relative to normal colonic epithelium, and demonstrate OTUD4 depletion enhances proliferation, clonogenicity, migration, and invasion in CRC cell lines, consistent with tumor-suppressive activity. Mechanistically, OTUD4 interacts with and deubiquitinates p53, thereby stabilizing this tumor suppressor protein and enhancing its transcriptional activity. Critically, p53 knockdown abrogates OTUD4-mediated suppression of malignant phenotypes, establishing the OTUD4-p53 axis as a critical regulatory node in CRC. Our findings identify OTUD4 as a novel tumor suppressor that constrains colorectal carcinogenesis through deubiquitinating and stabilizing p53, highlighting its therapeutic potential and warranting deeper investigation of OTUD4 in cancer biology.