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Coordinated DNA 5-mC and RNA m5C methylation epigenetically regulates MZF1 splice variants to drive EGFR-TKI

Huan Zhang1,2, Yutong Pang1,2, Bin Liu1

  • 1Cancer Research Center, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.

Experimental & Molecular Medicine
|June 30, 2026
PubMed

Insights

Myeloid zinc finger 1 (MZF1) splice variants drive resistance to EGFR-TKIs in lung cancer. Targeting epigenetic regulation of MZF1 splicing resensitizes resistant cells, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Research

Background:

  • Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a major clinical challenge in non-small-cell lung cancer (NSCLC).
  • Myeloid zinc finger 1 (MZF1) plays a role in regulating EGFR signaling, and its splice variants (MZF1^S and MZF1^L) show differential expression in resistant versus sensitive NSCLC patients.
  • The mechanisms controlling the differential expression of MZF1 splice variants in EGFR-TKI resistance are not well understood.

Purpose of the Study:

  • To elucidate the epigenetic mechanisms regulating MZF1 alternative splicing in the context of EGFR-TKI resistance.
  • To investigate the role of RNA and DNA methylation in controlling MZF1 splice variant production.
  • To evaluate the therapeutic potential of targeting the identified epigenetic regulators for overcoming EGFR-TKI resistance.

Main Methods:

  • Analysis of MZF1 splice variant expression in resistant and sensitive NSCLC patient cohorts.
  • Investigation of RNA m5C methylation using NSUN7/YBX1 and its impact on MZF1 pre-mRNA splicing.
  • Characterization of epigenetic modifications (DNA 5-methylcytosine) in the MZF1 5'-untranslated region.
  • Functional studies involving targeting the UHRF1/DNMT1-NSUN7/YBX1 axis to modulate splice variant expression and restore drug sensitivity.

Main Results:

  • NSUN7/YBX1-mediated RNA m5C methylation was identified as a key driver of resistance by promoting MZF1^S production.
  • Differential expression of MZF1^L (sensitive) and MZF1^S (resistant) is regulated by coordinated epigenetic control involving RNA and DNA methylation.
  • A UHRF1/DNMT1-NSUN7/YBX1 axis was found to synergistically regulate MZF1 splice variant selection.
  • Targeting this axis suppressed MZF1^S, restored MZF1^L, and resensitized resistant cells to EGFR-TKIs.

Conclusions:

  • A dual-layer epigenetic mechanism involving RNA and DNA methylation governs MZF1 alternative splicing and contributes to EGFR-TKI resistance.
  • Methylation-regulated MZF1 splice variants represent potential biomarkers for predicting resistance.
  • Targeting the identified epigenetic axis offers a promising therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.

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