Oxidative Stress-Mediated RUNX3 Mislocalization Occurs Via Jun Activation Domain-Binding Protein 1 and Histone...

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Runt domain transcription factor 3 (RUNX3) is a tumor suppressor frequently inactivated in various cancers.
• Inactivation mechanisms include mutations, epigenetic repression, and mislocalization to the cytoplasm.
• The role of oxidative stress in RUNX3 inactivation requires further investigation.

Purpose of the Study:

• To investigate the association between oxidative stress and RUNX3 nuclear-to-cytoplasmic mislocalization.
• To elucidate the role of histone modifications in mediating this stress-induced event.
• To identify key molecular players involved in RUNX3 inactivation under oxidative stress.

Main Methods:

• Analysis of histone modification enzymes (HDAC, HAT, MLL, EHMT2/G9a) under oxidative stress.
• Assessment of RUNX3 phosphorylation, Src activation, and JAB1 expression.
• Evaluation of RUNX3 localization using knockdown of HDAC and G9a.

Main Results:

• Oxidative stress increased histone deacetylase (HDAC) and EHMT2/G9a levels, while decreasing histone acetyltransferase and MLL levels.
• Oxidative stress induced RUNX3 phosphorylation, Src activation, and JAB1 expression.
• Knockdown of HDAC and G9a inhibited these stress-induced changes and restored RUNX3 nuclear localization.

Conclusions:

• Oxidative stress triggers epigenetic changes, including altered histone modifications.
• These modifications promote RUNX3 cytoplasmic mislocalization, phosphorylation, and inactivation via Src and JAB1.
• Targeting HDAC and G9a may offer a therapeutic strategy to restore RUNX3 function in cancer.