N⁷-methylguanosine (m⁷G) tRNA modification: a novel autophagy modulator in cancer

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Autophagy is a key process in tumorigenesis, regulated by genetic and epigenetic factors.
• Aberrant RNA modifications are increasingly linked to dysregulated autophagy and cancer development.
• The specific role of RNA modifications in cancer autophagy remains largely undefined.

Purpose of the Study:

• To investigate the function of tRNA m7G methyltransferase components METTL1 and WDR4 in esophageal squamous cell carcinoma (ESCC).
• To elucidate the mechanism by which METTL1 and WDR4 regulate MTORC1-mediated autophagy in ESCC.
• To explore the therapeutic potential of targeting the METTL1/WDR4 axis in ESCC.

Main Methods:

• Analysis of METTL1 and WDR4 expression in ESCC tissues and correlation with patient prognosis.
• Investigating the impact of targeting METTL1 or WDR4 on m7G-modified tRNA levels and oncogenic transcript translation.
• Examining the effects on MTORC1 signaling, ULK1 phosphorylation, and autophagy activation.
• Assessing the consequence of METTL1/WDR4 targeting on ESCC cell death.

Main Results:

• METTL1 and WDR4 are overexpressed in ESCC and associated with poor prognosis.
• Targeting METTL1/WDR4 reduces m7G-modified tRNAs and downregulates oncogenic transcripts, including MTOR pathway genes.
• This leads to hyperactivated MTORC1-mediated autophagy via ULK1 dephosphorylation.
• Inhibition of METTL1 or WDR4 induces cell death in ESCC.

Conclusions:

• METTL1 and WDR4 function as negative regulators of MTORC1-mediated autophagy in ESCC.
• tRNA m7G modification by METTL1/WDR4 influences the translation of specific oncogenic transcripts.
• The METTL1-mediated axis represents a novel regulatory mechanism linking translation and autophagy, presenting a potential therapeutic target for ESCC.