title: Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma.
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.
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Chung-Hsien
authors.initials: CH
authors.lastname: Li
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Yen
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Yen-Fu
authors.initials: YF
authors.lastname: Chen
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Kuo-Jui
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Fang
authors.affiliation: Department of Cancer Biology, Wake Forest Cancer Center, Wake Forest University, Winston-Salem, NC.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Division of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli, 35053, Taiwan.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology, Wake Forest Cancer Center, Wake Forest University, Winston-Salem, NC.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.affiliation: Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.|Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
authors.forename: Yi-Ming
authors.identifier: 0000-0002-6068-4964
authors.initials: YM
authors.lastname: Arthur Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D050938:Glycine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D020662:Guanine Nucleotide Exchange Factors; C490712:PREX2 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C494510:GNMT protein, human; D050938:Glycine N-Methyltransferase; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: GNMT; HCC; HectH9; PREX2