Related Experiment Video

Updated: Mar 6, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors

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METTL3 Methylation Induces Decay of Endogenous Retroelement Transcripts to Promote Tumor Immune Evasion

Xiaowei She1, Jingqin Lan2, Haokun Zhang1

  • 1Gastrointestinal Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Cancer Research
|March 5, 2026
PubMed

Insights

Methylation of METTL3 (methyltransferase-like 3) at K513 is crucial for colorectal cancer progression. Targeting this pathway with therapies, combined with immune checkpoint blockade, shows promise for treating CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Colorectal cancer (CRC) recurrence and progression remain significant clinical issues.
  • Tumor microenvironment crosstalk with malignant cells promotes relapse.
  • Understanding these mechanisms is key to developing better CRC therapies.

Purpose of the Study:

  • To identify key molecular modifications driving CRC progression and recurrence.
  • To elucidate the mechanistic role of METTL3 methylation in the tumor immune microenvironment.
  • To explore novel therapeutic strategies targeting the identified pathway.

Main Methods:

  • Identified K513 di-methylation on METTL3 as a critical modification in CRC.
  • Determined SETD1A catalyzes METTL3 K513 methylation, enhancing RNA m⁶A deposition.
  • Investigated the E2F4/SETD1A/METTL3 axis induced by fluorouracil.

Main Results:

  • METTL3 methylation enhances binding to SAM, increasing RNA m⁶A deposition.
  • METTL3 methylation suppresses retroelements, impairing type I interferon responses and promoting immune evasion.
  • Targeting E2F4 or METTL3 methylation synergized with immune checkpoint blockade to inhibit tumor growth.

Conclusions:

  • Discovered a methylation-dependent mechanism regulating the tumor immune microenvironment in CRC.
  • METTL3 K513 methylation is a driver of CRC progression and immune evasion.
  • Targeting the E2F4/SETD1A/METTL3 axis offers a potential therapeutic strategy for CRC.

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