國家衛生研究院 NHRI:Item 3990099045/6206
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    题名: Functional characterization of Glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in hepatocellular carcinoma
    作者: Yen, CH;Lu, YC;Li, CH;Lee, CM;Chen, CY;Cheng, MY;Huang, SF;Chen, KF;Cheng, AL;Liao, LY;Lee, YH;Chen, YM
    贡献者: Institute of Molecular and Genomic Medicine
    摘要: Glycine N-methyltransferase (GNMT) is a tumor suppressor for hepatocellular carcinoma (HCC). High rate of Gnmt knockout mice developed HCC. Epigenetic alteration and dysregulation of several pathways including Wnt, MPAK and JAK-STAT are associated with the HCC development in Gnmt knockout mice. We hypothesized that GNMT may regulate signal transduction through interacting with other proteins directly. In this report, we identified an mTOR inhibitor-DEPDC6/DEPTOR as a GNMT-binding protein using yeast two-hybrid screening. Fluorescence resonance energy transfer assay demonstrated that the C-terminal half of GNMT interact with the PDZ domain of DEPDC6/DEPTOR. Immunohistochemical staining showed that 27.5% (14/51) of HCC patients had higher expression level of DEPDC6/DEPTOR in the tumorous tissues than its tumor-adjacent tissues, especially among HCC patients with hepatitis B viral infection (Odds ratio = 10.3, 95% CI: 1.05 - 11.3) or patients with poor prognosis (Death Hazard ratio = 4.51, 95% CI = 1.60 - 12.7). In terms of molecular mechanism, knockdown of DEPDC6/DEPTOR expression in HuH-7 cells caused S6K and 4E-BP activation, but suppressed Akt. Overexpression of DEPDC6/DEPTOR activated Akt and increased survival of HCC cells. Overexpression of GNMT caused activation of mTOR/raptor downstream signaling and delayed G2/M cell cycle progression which altogether resulted in cellular senescence. Furthermore, GNMT reduced proliferation of HuH-7 cells and sensitized them to rapamycin treatment both in vitro and in vivo. In conclusion, GNMT regulates HCC growth in part through interacting with DEPDC6/DEPTOR and modulating mTOR/Raptor signaling pathway. Both GNMT and DEPDC6/DEPTOR are potential targets for the development of therapeutics for HCC.
    日期: 2012-03
    關聯: Molecular Medicine. 2012 Mar:18(3):286-296.
    Link to: http://dx.doi.org/10.2119/molmed.2011.00331
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1076-1551&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000303962700016
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84860855581
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