BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through bim induction

Amish J. Patel, Chung Ping Liao, Zhiguo Chen, Chiachi Liu, Yong Wang, Lu Q. Le

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51 引文 斯高帕斯(Scopus)

摘要

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 representa paradigm shift in therapy for MPNST patients.Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibitioncan shift this balance in favor of cancer cell apoptosis.
原文英語
頁(從 - 到)81-92
頁數12
期刊Cell Reports
6
發行號1
DOIs
出版狀態已發佈 - 2014

ASJC Scopus subject areas

  • 生物化學、遺傳與分子生物學 (全部)

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