RNF6 promotes colorectal cancer by activating the Wnt/b-catenin pathway via ubiquitination of TLE3

Lei Liu, Yanquan Zhang, Chi Chun Wong, Jingwan Zhang, Yujuan Dong, Xiangchun Li, Wei Kang, Francis K.L. Chan, Joseph J.Y. Sung, Jun Yu

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Gene amplification is a hallmark of cancer and is frequently observed in colorectal cancer. Previous whole-genome sequencing of colorectal cancer clinical specimens identified amplification of Ring finger protein 6 (RNF6), a RING-domain E3 ubiquitin ligase. In this study, we showed that RNF6 is upregulated in 73.5% (147/200) of patients with colorectal cancer and was positively associated with RNF6 gene amplification. Furthermore, RNF6 expression and its gene amplification were independent prognostic factors for poor outcome of patients with colorectal cancer. RNF6 promoted cell growth, cell-cycle progression, and epithelial-to-mesenchymal transition in colorectal cancer cells; RNF6 also promoted colorectal tumor growth and lung metastasis in mouse models. Mechanistic investigations revealed that RNF6 bound and ubiquitylated transducin-like enhancer of split 3 (TLE3), a transcriptional repressor of the b-catenin/TCF4 complex. RNF6-mediated degradation of TLE3 significantly suppressed the association of TLE3 with TCF4/LEF, which in turn led to recruitment of b-catenin to TCF4/LEF, triggering Wnt/b-catenin activation. Restoration of TLE3 expression abolished the oncogenic effects of RNF6. Taken together, these results demonstrate that RNF6 plays a pivotal oncogenic role in colorectal tumorigenesis. Significance: RNF6-mediated ubiquitination and degradation of TLE3 activates the Wnt/b-catenin pathway in colorectal carcinogenesis.

Original languageEnglish
Pages (from-to)1958-1971
Number of pages14
JournalCancer Research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

Bibliographical note

Publisher Copyright:
© 2018 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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