Journal
CELL REPORTS
Volume 6, Issue 1, Pages 81-92Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2013.12.001
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Funding
- Children Tumor Foundation
- Burroughs Wellcome Fund
- Dermatology Foundation, Disease-Oriented Clinical Scholar Program, National Cancer Institute of the National Institutes of Health [R01 CA166593]
- U.S. Department of Defense [W81XWH-12-1-0161]
- NATIONAL CANCER INSTITUTE [R01CA166593] Funding Source: NIH RePORTER
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Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized an MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of a chromatin regulator, Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.
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