Systemic control of HNF1B-driven redox homeostasis by N6-adenosine methylation

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Transcription factors regulate gene expression but are difficult drug targets.
• RNA modifications like N6-methyladenosine (m6A) influence cellular functions.
• The role of m6A in transcription factor regulation and cancer is not fully understood.

Purpose of the Study:

• To investigate the role of m6A methylation in regulating the transcription factor HNF1B.
• To determine the impact of the METTL3/METTL14 complex on HNF1B expression and function.
• To explore the link between m6A-mediated HNF1B regulation and cancer cell redox homeostasis.

Main Methods:

• Investigated m6A modification of HNF1B mRNA using genetic and chemical inhibition of METTL3.
• Assessed the impact of m6A depletion on HNF1B expression and glutathione metabolism.
• Evaluated cancer cell vulnerability to oxidative stress following disruption of the METTL3-HNF1B axis.

Main Results:

• METTL3/METTL14 complex deposits m6A marks on HNF1B mRNA, stabilizing its expression.
• Inhibition of m6A modification disrupts HNF1B-driven glutathione metabolism.
• Cancer cells lacking m6A or HNF1B exhibit impaired antioxidant capacity and increased sensitivity to oxidative stress.

Conclusions:

• m6A methylation directly regulates HNF1B, which is essential for redox homeostasis in cancer.
• The METTL3-HNF1B axis represents a metabolic vulnerability in cancer.
• Targeting the METTL3-HNF1B pathway offers a potential strategy for m6A-directed cancer therapies.