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Dissecting the effects of METTL3 on alternative splicing in prostate cancer

Lin Wang1,2, Ling Shi2, Yonghao Liang2

  • 1Metabolic Disease Research Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.

Frontiers in Oncology
|September 7, 2023
PubMed

Insights

METTL3 regulates alternative splicing (AS) in prostate cancer (PCa) by affecting exon skipping and intron retention. METTL3-dependent AS events, influenced by N6-methyladenosine (m6A), highlight MKNK2 AS events as potential PCa biomarkers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • METTL3's role in cancer is known, but its function in prostate cancer (PCa) isoform switching via alternative splicing (AS) remains understudied.
  • Prostate cancer exhibits significant heterogeneity, with androgen-sensitive and resistant subtypes potentially displaying distinct molecular mechanisms.

Purpose of the Study:

  • To investigate the role of METTL3 in regulating alternative splicing (AS) in prostate cancer (PCa).
  • To explore the impact of METTL3 depletion on AS events in different PCa subtypes.
  • To identify potential prognostic biomarkers associated with METTL3-regulated AS in PCa.

Main Methods:

  • Utilized standard RNA-sequencing and long-read direct RNA-sequencing (Oxford Nanopore).
  • Analyzed genome-wide METTL3-regulated alternative splicing events in two distinct PCa cell lines.
  • Investigated the dependence of METTL3-regulated AS on N6-methyladenosine (m6A) and splicing factors.

Main Results:

  • METTL3 depletion induced differential AS events (exon skipping, intron retention) in androgen-sensitive versus resistant PCa cell lines, indicating AS heterogeneity.
  • METTL3-regulated AS is dependent on m6A modification and specific splicing factors.
  • Identified cell type-specific AS signatures for genes like MKNK2, crucial for PCa tumorigenesis.
  • Validated the clinical relevance of MKNK2 AS events in PCa patients, suggesting an m6A-mediated regulatory mechanism involving SRSF1.

Conclusions:

  • METTL3 plays a significant role in regulating PCa-associated alternative splicing programs.
  • The findings expand the understanding of METTL3's function in tumorigenesis.
  • MKNK2 alternative splicing events represent a promising novel prognostic biomarker for prostate cancer.
Keywords:
METTL3MKNK2N 6 -methyladenosineRNA splicingnanopore direct RNA sequencingprostate cancer

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