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

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

  • J Exp Clin Cancer Res. 2022 Nov 11;41(1):321. doi: 10.1186/s13046-022-02530-y.
Matthew J Kling 1 2,  Varun Kesherwani 2,  Nitish K Mishra 3,  Gracey Alexander 4,  Erin M McIntyre 4,  Sutapa Ray 2 4,  Kishore B Challagundla 5,  Shantaram S Joshi 3,  Don W Coulter 2 4,  Nagendra K Chaturvedi 6 7 8
Affiliations

Affiliations

  • 1 Department of Oral Biology, Creighton University, School of Dentistry, Omaha, NE, 68102, USA.
  • 2 Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • 3 Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • 4 Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • 5 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
  • 6 Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, 68198, USA. nchaturvedi@unmc.edu.
  • 7 Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE, 68198, USA. nchaturvedi@unmc.edu.
  • 8 Department of Pediatrics, Hematology and Oncology Division, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, 68198, USA. nchaturvedi@unmc.edu.
PMID: 36357906 DOI: 10.1186/s13046-022-02530-y
Abstract

Background: Medulloblastoma (MB) patients with MYC oncogene amplification or overexpression exhibit extremely poor clinical outcomes and respond poorly to current therapies. Epigenetic deregulation is very common in MYC-driven MB. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs. This study aimed to investigate the therapeutic potential of inhibiting the BET proteins and HDACs together in MB.

Methods: Using clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat), we evaluated the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts and examined underlying molecular mechanism(s).

Results: Co-treatment of JQ1 or OTX015 with panobinostat synergistically suppressed growth/survival of MYC-amplified MB cells by inducing G2 cell cycle arrest and Apoptosis. Mechanistic investigation using RNA-seq revealed that co-treatment of JQ1 with panobinostat synergistically modulated global gene expression including MYC/HDAC targets. Syk and MSI1 oncogenes were among the top 50 genes synergistically downregulated by JQ1 and panobinostat. RT-PCR and western blot analyses confirmed that JQ1 and panobinostat synergistically inhibited the mRNA and protein expression of MSI1/Syk along with MYC expression. Reduced Syk/MSI expression after BET (specifically, BRD4) gene-knockdown further confirmed the epigenetic regulation of Syk and MSI1 genes. In addition, the combination of OTX015 and panobinostat significantly inhibited tumor growth in MYC-amplified MB xenografted mice by downregulating expression of MYC, compared to single-agent therapy.

Conclusions: Together, our findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB.

Keywords

BET proteins; BET-HDAC inhibitors; Gene transcription; HDACs; MYC; Medulloblastoma.

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