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

AmishJ Patel, Chung Ping Liao, Zhiguo Chen, Chiachi Liu, Yong Wang, LuQ Le

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)81-92
Number of pages12
JournalCell Reports
Volume6
Issue number1
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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