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METTL3 potentiates resistance to cisplatin through m6 A modification of TFAP2C in seminoma

Jingchao Wei1, Yinghao Yin2, Jun Zhou2

  • 1Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Journal of Cellular and Molecular Medicine
|August 29, 2020
PubMed

Insights

Cisplatin resistance in seminoma, the most common male cancer in young adults, involves N6-methyladenosine (m6A) modifications. Targeting m6A regulators may overcome chemotherapy resistance by stabilizing TFAP2C mRNA and enhancing DNA repair.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Testicular germ cell tumours (TGCTs) are the most common cancer in men aged 20-34, with seminomas being the predominant subtype.
  • Cisplatin is a key chemotherapy agent, but resistance can develop through complex mechanisms, impacting treatment efficacy even in highly curable cancers like seminoma.
  • Epigenetic modifications, including non-coding RNA interactions and N6-methyladenosine (m6A) methylation, are implicated in cellular responses to chemotherapy.

Purpose of the Study:

  • To investigate the role of m6A epigenetic modifications in cisplatin resistance in seminoma.
  • To explore the functional interaction between m6A machinery, specifically methyltransferase-like protein 3 (METTL3) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and transcription factor-activating enhancer-binding protein 2C (TFAP2C) in cisplatin-resistant seminoma cells.
  • To elucidate the downstream effects of TFAP2C modulation on seminoma cell survival under cisplatin treatment.

Main Methods:

  • Establishment of cisplatin-resistant seminoma cell lines (TCam-2/CDDP).
  • Global m6A enrichment analysis in sensitive and resistant seminoma cells.
  • Investigation of TFAP2C mRNA modification by METTL3 and its interaction with IGF2BP1.
  • Assessment of TFAP2C mRNA stability and its impact on DNA repair gene expression and cell survival under cisplatin exposure.

Main Results:

  • Global m6A enrichment patterns were characterized in cisplatin-sensitive and resistant seminoma cells.
  • TFAP2C mRNA was identified as a target of m6A modification by METTL3, with IGF2BP1 acting as an m6A reader.
  • Enhanced stability of TFAP2C mRNA was observed in cisplatin-resistant cells, leading to increased expression of DNA repair-related genes and promoting cell survival.
  • TFAP2C appears to play a crucial role in the cellular adaptation to cisplatin treatment in seminoma.

Conclusions:

  • m6A epigenetic modifications are involved in the development of cisplatin resistance in seminoma.
  • The METTL3-m6A-IGF2BP1-TFAP2C axis contributes to seminoma cell survival under cisplatin stress, likely through the upregulation of DNA repair mechanisms.
  • Targeting m6A methylation pathways presents a potential therapeutic strategy to overcome cisplatin resistance in seminoma, improving treatment outcomes for this malignancy.
Keywords:
METTL3TFAP2Cchemoresistancem6Aseminoma

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