Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma
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Sujatha Venkataraman1*, Irina Alimova1*, Ilango Balakrishnan1, Peter Harris1, Diane K Birks2, Andrea Griesinger1, Vladimir Amani1, Brian Cristiano1, Marc Remke3, Michael D Taylor3, Michael Handler2, Nicholas K Foreman1 and Rajeev Vibhakar1
1 Department of Pediatrics, Children’s Hospital Colorado and University of Colorado, Denver, CO, USA
2 Department of Neurosurgery, Children’s Hospital Colorado and University of Colorado, Denver, CO, USA
3 Division of Neurosurgery, Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, ON, Canada
* These two authors contributed equally to this work.
Rajeev Vibhakar, e-mail: [email protected]
Keywords: Medulloblastoma, MYC, BRD4, JQ1, Senescence
Received: December 05, 2013 Accepted: March 19, 2014 Published: March 31, 2014
Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.
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