TRIM67 activates p53 to suppress colorectal cancer initiation and progression
Publication in refereed journal


Times Cited
Altmetrics Information
.

Other information
AbstractTripartite motif (TRIM) family proteins participate in a variety of important cellular processes, including apoptosis, cell-cycle arrest, DNA repair, and senescence. In this study, we demonstrated that a novel TRIM family member, TRIM67, was commonly silenced in colorectal cancer and its downregulation was associated with poor survival. Trim67 knockout in Apc(Min/+) mice increased the incidence, multiplicity, and burden of colorectal tumors. Similarly, colon-specific knockout of Trim67 significantly accelerated azoxymethane-induced colorectal cancer in mice. RNA sequencing revealed that the anti-tumor effect of TRIM67 was mediated by activation of the p53 signaling pathway. TRIM67 interacted directly with the C-terminus of p53, inhibiting p53 degradation by its ubiquitin ligase MDM2. TRIM67 was also a transcriptional target of p53; upon cellular stress, p53 bound to the TRIM67 promoter and induced significant upregulation of TRIM67, thereby forming a TRIM67/p53 self-amplifying loop that boosts p53-induced cell growth inhibition and apoptosis. Consequently, loss of this p53-positive regulatory program profoundly compromised p53-mediated responses to chemotherapy-induced DNA damage. Dampened p53 response was also observed in tumors of Trim67 knockout mice and Trim67 knockout embryonic fibroblasts. TRIM67 reactivation restored p53 activation and sensitized colorectal cancer cells to chemotherapy in vitro and in vivo. TRIM67 thus functions as a pivotal tumor suppressor in colorectal cancer and is a potential target for improving chemotherapy responsiveness.
Acceptance Date21/06/2019
All Author(s) ListShiyan Wang, Yanquan Zhang, Junzhe Huang, Chi Chun Wong, Jianning Zhai, Chuangen Li, Guifeng Wei, Liuyang Zhao, Guoping Wang, Hong Wei, Zengren Zhao, Jun Yu
Journal nameCancer Research
Year2019
Month8
Volume Number79
Issue Number16
PublisherAmerican Association for Cancer Research
Pages4086 - 4098
ISSN0008-5472
eISSN1538-7445
LanguagesEnglish-United States

Last updated on 2020-31-05 at 02:28