RUNX3 methylation drives hypoxia-induced cell proliferation and antiapoptosis in early tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Tumor suppressor RUNX3 inactivation is crucial in early tumorigenesis.
• The precise posttranslational modification (PTM) mechanisms of RUNX3 inactivation under hypoxia remain unclear.

Purpose of the Study:

• To elucidate the role of G9a, a lysine-specific methyltransferase (KMT), in modulating RUNX3 activity via PTM under hypoxic conditions.
• To investigate the impact of G9a-mediated RUNX3 methylation on cancer cell proliferation, immune response, and apoptosis.

Main Methods:

• Assessed G9a protein levels and its interaction with RUNX3 under hypoxia.
• Quantified RUNX3 methylation at K129 and K171 residues.
• Evaluated the effects of RUNX3 methylation on cofactor interactions (CBFβ, p300) and acetylation.
• Analyzed the influence of G9a-mediated RUNX3 methylation on cell cycle, cell division, immune response, and apoptosis.

Main Results:

• Hypoxia significantly increased G9a protein levels and its interaction with the RUNX3 Runt domain.
• G9a-mediated methylation of RUNX3 at K129 and K171 was observed under hypoxia.
• Methylation inactivated RUNX3 by reducing interactions with CBFβ and p300, and decreased p300-mediated acetylation.
• G9a-mediated RUNX3 methylation promoted cancer cell proliferation and suppressed immune response and apoptosis.

Conclusions:

• A novel mechanism of RUNX3 inactivation by G9a-mediated methylation under hypoxia was identified.
• This pathway promotes cancer cell proliferation and anti-apoptosis, contributing to early tumorigenesis.
• Targeting G9a-mediated RUNX3 methylation presents a potential therapeutic strategy for controlling tumor growth.