Medical

This study aimed to investigate the therapeutic potential of dual-inhibition targeting BET proteins and HDACs in treating MYC-amplified Medulloblastoma (MB), which is associated with poor clinical outcomes and unresponsiveness to current therapies. The bromodomain extra-terminal (BET) proteins and histone deacetylases (HDACs) are epigenetic regulators of MYC transcription and its associated tumorigenic programs.

The study used clinically relevant BET inhibitors (JQ1 or OTX015) and a pan-HDAC inhibitor (panobinostat) to evaluate the effects of combined inhibition on cell growth/survival in MYC-amplified MB cell lines and xenografts, and examined the underlying molecular mechanism(s). The researchers determined the single agent and combined efficacies of these inhibitors on MB cell growth, apoptosis, and cell cycle using MTT, Annexin-V, and propidium-iodide staining assays. They investigated the underlying mechanisms of these efficacies using RNA-seq, siRNA-transfection, RT-PCR, and western blot analyses. In vivo antitumor efficacies were evaluated using subcutaneously MB-bearing xenografts.

The findings of the study revealed that 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 the expression of MYC, compared to single-agent therapy. Together, these findings demonstrated that dual-inhibition of BET and HDAC proteins of the epigenetic pathway can be a novel therapeutic approach against MYC-driven MB. The findings demonstrate the synergistic effects of this combination therapy in suppressing MB cell growth and survival, providing valuable insights into potential treatment strategies for MYC-driven MB and highlighting the importance of epigenetic regulation in this context. This is a significant finding that could lead to the development of new treatments for this devastating disease.

Author(s) Details:

Matthew J. Kling,
Department of Oral Biology, Creighton University, School of Dentistry, Omaha, NE 68102, USA and Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Varun Kesherwani,
Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Nitish K. Mishra,
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Gracey Alexander,
Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Erin M. McIntyre,
Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Sutapa Ray,
Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA and Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Kishore B. Challagundla,
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Shantaram S. Joshi,
Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Don W. Coulter,
Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA and Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Nagendra K. Chaturvedi,
Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA and Department of Pediatrics, Hematology/Oncology Division, University of Nebraska Medical Center, Omaha, NE 68198, USA and Department of Pediatrics, Hematology and Oncology Division, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE 68198, USA.

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