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BRD4 regulates m6A of ESPL1 mRNA via interaction with ALKBH5 to modulate breast cancer progression

Haisheng Zhang1, Linlin Lu2, Cheng Yi1

  • 1Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery; State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

Acta Pharmaceutica Sinica. B
|May 15, 2025
PubMed

Insights

Targeting bromodomain-containing protein 4 (BRD4) inhibits breast cancer (BC) by increasing AlkB homolog 5 (ALKBH5) demethylase activity. This pathway impacts RNA methylation and BC cell malignancy.

Area of Science:

  • Epigenetics
  • RNA biology
  • Cancer research

Background:

  • The interplay between RNA methylation and chromatin modification is poorly understood.
  • Bromodomain-containing protein 4 (BRD4) is implicated in cancer, but its role in RNA methylation is unclear.

Purpose of the Study:

  • To investigate the functional relationship between BRD4, RNA m6A modification, and breast cancer (BC) progression.
  • To elucidate the molecular mechanisms linking BRD4 inhibition to BC suppression.

Main Methods:

  • Utilized siRNA and small molecule inhibitor (JQ1) to target BRD4 in breast cancer cells.
  • Investigated mRNA m6A levels, protein expression (ALKBH5, TRIM21, IGF2BP3), mRNA stability, and ubiquitination.
  • Employed RNA-binding protein immunoprecipitation (RIP) and analyzed 3' UTR interactions.
  • Conducted animal studies and analyzed clinical samples.

Main Results:

  • BRD4 inhibition (siRNA or JQ1) decreased global mRNA m6A levels and suppressed BC cell malignancy.
  • BRD4 inhibition upregulated AlkB homolog 5 (ALKBH5) via increased mRNA stability mediated by RALY binding to ALKBH5 3' UTRs.
  • BRD4 acts as a scaffold for TRIM21 and ALKBH5, promoting ALKBH5 ubiquitination and degradation; inhibition disrupts this.
  • Increased ALKBH5 demethylated ESPL1 mRNA, reducing IGF2BP3 binding and leading to ESPL1 mRNA decay.
  • The BRD4/ALKBH5/ESPL1 pathway is critical for BC progression in preclinical and clinical settings.

Conclusions:

  • BRD4 inhibition represents a potential therapeutic strategy for breast cancer by modulating RNA methylation.
  • This study reveals a novel crosstalk between histone modification (via BRD4) and RNA methylation (via ALKBH5).
  • The findings highlight the BRD4/ALKBH5/ESPL1 axis as a key regulator in breast cancer pathogenesis.
Keywords:
ALKBH5BRD4Breast cancerCell cycleESPL1RALYTRIM21m6A

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