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METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS

Jie-Xun Chen1, Dong-Ming Chen1, Dong Wang1

  • 1Department of Urology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China.

Oncology Reports
|March 24, 2023
PubMed

Insights

Methyltransferase-like 3 (METTL3) promotes bladder cancer (BCa) by methylating RRAS mRNA, leading to tumor growth and metastasis. Targeting the METTL3/RRAS/YTHDF2 pathway offers a potential diagnostic and therapeutic strategy for BCa.

Area of Science:

  • Molecular Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Bladder cancer (BCa) is a significant health concern with complex tumorigenesis.
  • The role of RNA methylation, specifically N6-methyladenosine (m6A), in cancer development is an emerging area of research.
  • Methyltransferase-like 3 (METTL3) is an m6A writer enzyme implicated in various cancers.

Purpose of the Study:

  • To investigate the role of METTL3-mediated methylation of RAS related (RRAS) mRNA in bladder cancer (BCa) tumorigenesis and progression.
  • To elucidate the regulatory axis involving METTL3, RRAS, and YTH N6-methyladenosine (m6A) RNA binding protein 2 (YTHDF2) in BCa.
  • To assess the potential of targeting this axis for BCa diagnosis and therapy.

Main Methods:

  • Quantification of METTL3 expression in BCa tissues and cell lines using RT-qPCR and Western blot.
  • Bioinformatic analysis using TCGA and GEPIA databases to correlate METTL3 expression with clinical characteristics.
  • In vitro and in vivo cellular experiments to assess the impact of METTL3 on BCa cell proliferation, migration, and invasion.
  • Methylated RNA immunoprecipitation (MeRIP)-qPCR and dual-luciferase reporter assays to confirm the METTL3/RRAS/YTHDF2 regulatory pathway.

Main Results:

  • METTL3 expression was significantly upregulated in BCa specimens and cell lines, correlating with unfavorable clinical features.
  • METTL3 silencing suppressed the proliferative, migratory, and invasive capacities of BCa cells in vitro and in vivo.
  • METTL3 directly binds to m6A sites on RRAS mRNA, leading to suppressed RRAS expression.
  • YTHDF2 recognizes m6A-modified RRAS mRNA, mediating its degradation.
  • The METTL3/RRAS/YTHDF2 axis promotes BCa growth and metastasis by downregulating RRAS.

Conclusions:

  • METTL3-catalyzed m6A modification plays a critical role in bladder cancer tumorigenesis and development.
  • The METTL3/RRAS/YTHDF2 regulatory pathway facilitates BCa progression by suppressing RRAS expression in an m6A YTHDF2-dependent manner.
  • Targeting the METTL3/RRAS/YTHDF2 axis represents a promising therapeutic strategy for bladder cancer.
Keywords:
N6‑methyladenosineRAS relatedbladder cancermalignant progressionmethyltransferase‑like 3

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