Characterization of the GNMT‐HectH9‐PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma |
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| Authors: | Yen‐Fu Chen Kuo‐Jui Lee Cheng‐Chieh Fang Xian Zhang Chih‐Chung Lai Shiu‐Feng Huang Hui‐Kuan Lin Yi‐Ming Arthur Chen |
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| Affiliation: | 1. Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, Taiwan;2. Department of Cancer Biology, Wake Forest Cancer Center, Wake Forest University, Winston‐Salem, NC;3. Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, Taiwan;4. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;5. Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan |
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| 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. |
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| Keywords: | GNMT HCC HectH9 PREX2 |
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