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Updated: Aug 22, 2025

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A novel dual epigenetic approach targeting BET proteins and HDACs in Group 3 (MYC-driven) Medulloblastoma

Matthew J Kling1,2, Varun Kesherwani2, Nitish K Mishra3

  • 1Department of Oral Biology, Creighton University, School of Dentistry, Omaha, NE, 68102, USA.

Journal of Experimental & Clinical Cancer Research : CR
|November 11, 2022
PubMed
Abstract

Insights

Dual inhibition of BET proteins and histone deacetylases (HDACs) synergistically targets MYC-driven medulloblastoma. This combination therapy suppressed tumor growth by downregulating MYC and other oncogenes, offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • MYC oncogene amplification in medulloblastoma (MB) leads to poor outcomes.
  • Epigenetic deregulation is common in MYC-driven MB.
  • BET proteins and HDACs regulate MYC transcription.

Purpose of the Study:

  • Investigate the combined therapeutic potential of inhibiting BET proteins and HDACs in MB.
  • Evaluate the efficacy of dual inhibition in MYC-amplified MB models.

Main Methods:

  • Utilized BET inhibitors (JQ1, OTX015) and a pan-HDAC inhibitor (panobinostat).
  • Assessed effects on cell growth, survival, cell cycle, and apoptosis in MB cell lines and xenografts.
  • Performed RNA-seq, RT-PCR, and western blot analyses to examine molecular mechanisms.

Main Results:

  • Combined BET and HDAC inhibition synergistically suppressed MB cell growth and survival.
  • Co-treatment induced G2 cell cycle arrest and apoptosis.
  • Downregulated MYC, SYK, and MSI1 oncogenes at mRNA and protein levels.
  • Significantly inhibited tumor growth in xenograft models.

Conclusions:

  • Dual inhibition of BET and HDAC proteins is a promising therapeutic strategy for MYC-driven MB.
  • This approach targets key epigenetic regulators of MYC-driven tumorigenesis.
Keywords:
BET proteinsBET-HDAC inhibitorsGene transcriptionHDACsMYCMedulloblastoma

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