title: BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction.
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 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.
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
authors.forename: Amish J
authors.initials: AJ
authors.lastname: Patel
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Liao
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
authors.forename: Chiachi
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA; Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA; UTSW Neurofibromatosis Clinic, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA. Electronic address: lu.le@utsouthwestern.edu.
authors.forename: Lu Q
authors.initials: LQ
authors.lastname: Le
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D063646:Carcinogenesis; D049109:Cell Proliferation; D016514:Genes, Neurofibromatosis 1; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C000606776:Bcl2l11 protein, mouse; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins