TRIM67 activates p53 to suppress colorectal cancer initiation and progression

Shiyan Wang, Yanquan Zhang, Junzhe Huang, Chi Chun Wong, Jianning Zhai, Chuangen Li, Guifeng Wei, Liuyang Zhao, Guoping Wang, Hong Wei, Zengren Zhao, Jun Yu

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

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-ApcMin/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.

Original languageEnglish
Pages (from-to)4086-4098
Number of pages13
JournalCancer Research
Volume79
Issue number16
DOIs
StatePublished - Aug 15 2019

Bibliographical note

Publisher Copyright:
©2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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