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.
Aim: The study explores the potential of dual-inhibition targeting BET proteins and HDACs, both of which play crucial roles in MYC transcription and tumorigenic programs.
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). Single agent and combined efficacies of these inhibitors on MB cell growth, apoptosis and cell cycle were determined using MTT, Annexin-V and propidium-iodide staining assays, respectively. Underlying mechanisms of these efficacies were investigated using RNA-seq, siRNA-transfection, RT-PCR and western blot analyses. In vivo antitumor efficacies were evaluated using subcutaneously MB-bearing xenografts.
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 panobi- nostat. 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 combi- nation 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. 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. On the other hand, 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,
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.
Please see the link here: https://stm.bookpi.org/ACMMR-V12/article/view/12974
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