TRIM67 activates p53 to suppress colorectal cancer initiation and progression

Tripartite motif (TRIM) family proteins participate in a a TRIM67/p53 self-amplifying loop that boosts p53-induced variety of important cellular processes, including apoptosis, cell growth inhibition and apoptosis. Consequently, loss of cell-cycle arrest, DNA repair, and senescence. In this study, we this p53-positive regulatory program profoundly compro-demonstrated that a novel TRIM family member, TRIM67, was mised p53-mediated responses to chemotherapy-induced commonly silenced in colorectal cancer and its downregula-DNA damage. Dampened p53 response was also observed in tion was associated with poor survival. Trim67 knockout in tumors of Trim67 knockout mice and Trim67 knockout embry-Apc^Min/þ mice increased the incidence, multiplicity, and bur-onic fibroblasts. TRIM67 reactivation restored p53 activation den of colorectal tumors. Similarly, colon-specific knockout of and sensitized colorectal cancer cells to chemotherapy in vitro Trim67 significantly accelerated azoxymethane-induced colo- and in vivo. TRIM67 thus functions as a pivotal tumor sup-rectal cancer in mice. RNA sequencing revealed that the anti-pressor in colorectal cancer and is a potential target for tumor effect of TRIM67 was mediated by activation of the p53 improving chemotherapy responsiveness. signaling pathway. TRIM67 interacted directly with the C-terminus of p53, inhibiting p53 degradation by its ubiquitin Significance: The TRIM67/p53 axis represents a novel ther-ligase MDM2. TRIM67 was also a transcriptional target of p53; apeutic target that could be harnessed to improve chemother-upon cellular stress, p53 bound to the TRIM67 promoter and apy efficacy in colorectal cancer expressing wild-type p53 but induced significant upregulation of TRIM67, thereby forming with repressed p53 signaling.