Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

Chung Hsien Li, Chia Hung Yen, Yen Fu Chen, Kuo Jui Lee, Cheng Chieh Fang, Xian Zhang, Chih Chung Lai, Shiu Feng Huang, Hui Kuan Lin, Yi Ming Arthur Chen

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The pathogenesis of hepatocellular carcinoma (HCC) involves many molecular pathways. Glycine N-methyltransferase (GNMT) is downregulated in almost all HCC and its gene knockout mice developed HCC with high penetrance. We identified PREX2, a novel PTEN inhibitor, as a GNMT-interacting protein. Such interaction enhanced degradation of PREX2 through an E3 ligase HectH9-mediated proteasomal ubiquitination pathway. Depletion of GNMT or HectH9 resulted in AKT activation in a PREX2 dependent manner and enhanced cell proliferation. An elevated PREX2 protein expression accompanied by activation of AKT was observed in the liver of Gnmt knockout mice. PREX2 protein expression was upregulated in 54.9% of human HCC samples, while its mRNA level was comparable in tumor and tumor-adjacent tissue, suggesting a post-translational alteration of PREX2 expression. Higher level of PREX2 in the tumor tissues was associated with poorer survival. These results reveal a novel mechanism in which GNMT participates in AKT signaling and HCC tumorigenesis by promoting HectH9-mediated PREX2 degradation.

Original languageEnglish
Pages (from-to)2284-2297
Number of pages14
JournalInternational Journal of Cancer
Volume140
Issue number10
DOIs
Publication statusPublished - May 15 2017
Externally publishedYes

Keywords

  • GNMT
  • HCC
  • HectH9
  • PREX2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Li, C. H., Yen, C. H., Chen, Y. F., Lee, K. J., Fang, C. C., Zhang, X., Lai, C. C., Huang, S. F., Lin, H. K., & Arthur Chen, Y. M. (2017). Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma. International Journal of Cancer, 140(10), 2284-2297. https://doi.org/10.1002/ijc.30652