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Functional characterization of glycine N-methyltransferase and its interactive protein DEPDC6/DEPTOR in

Chia-Hung Yen1, Yao-Cheng Lu, Chung-Hsien Li

  • 1AIDS Prevention and Research Center, National Yang-Ming University, Shih-Pai, Taipei, Taiwan.

Molecular Medicine (Cambridge, Mass.)
|December 14, 2011
PubMed

Insights

Glycine N-methyltransferase (GNMT) suppresses hepatocellular carcinoma (HCC). It interacts with DEPDC6/DEPTOR, modulating the mTOR/raptor pathway, offering new therapeutic targets for HCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Glycine N-methyltransferase (GNMT) acts as a tumor suppressor in hepatocellular carcinoma (HCC).
  • GNMT deficiency in mice leads to HCC development, associated with dysregulated Wnt, MAPK, and JAK-STAT pathways.
  • The precise molecular mechanisms by which GNMT suppresses HCC are not fully understood.

Purpose of the Study:

  • To investigate the potential of GNMT in regulating signal transduction through protein interactions.
  • To identify proteins that interact with GNMT and elucidate their role in HCC.
  • To explore GNMT and its interacting partners as potential therapeutic targets for HCC.

Main Methods:

  • Yeast two-hybrid screening to identify GNMT-binding proteins.
  • Fluorescence resonance energy transfer (FRET) assay to confirm protein interactions.
  • Immunohistochemical staining of HCC patient tissues to assess DEPDC6/DEPTOR expression.
  • Cell-based assays (siRNA knockdown, overexpression) to study molecular mechanisms.
  • In vitro and in vivo experiments to evaluate the effect of GNMT on HCC cells and rapamycin sensitivity.

Main Results:

  • DEP domain containing MTOR-interacting protein (DEPDC6/DEPTOR), an mTOR inhibitor, was identified as a GNMT-binding protein.
  • GNMT directly interacts with the PDZ domain of DEPDC6/DEPTOR.
  • Elevated DEPDC6/DEPTOR expression was observed in 37.5% of HCC tissues, particularly in patients with hepatitis B viral infection and poor prognosis.
  • DEPDC6/DEPTOR knockdown activated S6K and 4E-BP while suppressing Akt; conversely, DEPDC6/DEPTOR overexpression activated Akt and enhanced HCC cell survival.
  • GNMT overexpression activated mTOR/raptor signaling, delayed cell cycle progression, induced senescence, reduced HCC cell proliferation, and increased sensitivity to rapamycin.

Conclusions:

  • GNMT regulates HCC growth by interacting with DEPDC6/DEPTOR and modulating the mTOR/raptor signaling pathway.
  • Both GNMT and DEPDC6/DEPTOR represent promising therapeutic targets for HCC treatment.
  • Understanding the GNMT-DEPDC6/DEPTOR interaction provides insights into HCC pathogenesis and potential therapeutic strategies.

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