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Characterization of the GNMT‐HectH9‐PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma
Author(s) -
Li ChungHsien,
Yen ChiaHung,
Chen YenFu,
Lee KuoJui,
Fang ChengChieh,
Zhang Xian,
Lai ChihChung,
Huang ShiuFeng,
Lin HuiKuan,
Arthur Chen YiMing
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30652
Subject(s) - cancer research , protein kinase b , carcinogenesis , ubiquitin ligase , hepatocellular carcinoma , pten , pathogenesis , downregulation and upregulation , biology , pi3k/akt/mtor pathway , ubiquitin , signal transduction , cancer , microbiology and biotechnology , immunology , gene , genetics
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.