Characterization of the GNMT-HectH9-PREX2 tripartite relationship in the pathogenesis of hepatocellular carcinoma

Area of Science:

• Hepatocellular carcinoma (HCC) pathogenesis
• Molecular oncology
• Signal transduction pathways

Background:

• Glycine N-methyltransferase (GNMT) is frequently downregulated in hepatocellular carcinoma (HCC).
• GNMT gene knockout mice exhibit high penetrance of HCC.
• PREX2, a PTEN inhibitor, is implicated in cancer development.

Purpose of the Study:

• To elucidate the role of GNMT in HCC pathogenesis.
• To identify proteins interacting with GNMT.
• To investigate the mechanism by which GNMT influences AKT signaling and cell proliferation in HCC.

Main Methods:

• Protein-protein interaction studies to identify GNMT interactors.
• Ubiquitination assays to study protein degradation pathways.
• Western blotting and immunohistochemistry to assess protein expression in mouse models and human HCC samples.
• Analysis of AKT signaling pathway activation.
• Correlation analysis between PREX2 expression and patient survival.

Main Results:

• PREX2 was identified as a GNMT-interacting protein.
• GNMT promotes HectH9-mediated proteasomal degradation of PREX2.
• Depletion of GNMT or HectH9 leads to PREX2 accumulation, AKT activation, and enhanced cell proliferation.
• Elevated PREX2 protein levels and AKT activation were observed in Gnmt knockout mice livers.
• PREX2 protein upregulation, independent of mRNA levels, was found in human HCC tissues and correlated with poorer survival.

Conclusions:

• GNMT plays a crucial role in HCC tumorigenesis by regulating PREX2 stability.
• The GNMT-HectH9-PREX2 axis controls AKT signaling, impacting cell proliferation and HCC progression.
• Post-translational regulation of PREX2 by GNMT represents a novel mechanism in HCC development.