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A deregulated m6A writer complex axis driven by BRD4 confers an epitranscriptomic vulnerability in combined DNA

Xiao Lu1, Lichao Peng1, Jiancheng Ding2

  • 1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.

Proceedings of the National Academy of Sciences of the United States of America
|October 2, 2023
PubMed

Insights

BRD4 protein regulates the m6A writer complex, impacting cancer cell DNA repair and apoptosis. Targeting this pathway with BET and PARP inhibitors overcomes resistance in cancer treatment.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Aberrant expression of the m6A methyltransferase complex (MTC) is linked to human cancers.
  • The transcriptional regulation of MTC subunits and their role in tumorigenesis are not fully understood.

Purpose of the Study:

  • To investigate the interplay between BRD4 and the m6A writer complex in cancer.
  • To elucidate the functional consequences of this interaction on gene expression, DNA damage response, and therapeutic vulnerabilities.

Main Methods:

  • Analysis of BRD4's role in regulating MTC subunit expression across cancers.
  • Assessment of m6A modification dynamics upon BET inhibition.
  • Evaluation of combined BET and PARP inhibition in patient-derived xenograft models.

Main Results:

  • BRD4 directly stimulates the expression of seven MTC subunits, maintaining nuclear writer complex integrity.
  • BET inhibition leads to global m6A reduction, altering BRD4-dependent transcription and impairing DNA damage response (homologous recombination repair and apoptosis).
  • Combined BET/PARP inhibition disrupts m6A modification of key genes, overcoming PARP inhibitor resistance.

Conclusions:

  • A significant cross-talk exists between BRD4-mediated epigenetic regulation and MTC-driven epitranscriptomic networks in cancer.
  • This interplay presents a therapeutic vulnerability for combined DNA repair-targeted therapies.
  • Targeting the BRD4-MTC axis offers a promising strategy to counteract PARP inhibitor resistance.
Keywords:
BETDNA repairm6A

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