Journal article
BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells
EK Baker, S Taylor, A Gupte, PP Sharp, M Walia, NC Walsh, ACW Zannettino, AM Chalk, CJ Burns, CR Walkley
Scientific Reports | Published : 2015
DOI: 10.1038/srep10120
Abstract
Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Los..
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Funding Acknowledgements
We thank Peter Houghton (Nationwide Children's Hospital, Ohio) for generously sharing human OS xenograft material; SVH BioResources Centre; Assoc Prof Jock Campbell for assistance with statistical analyses; Ms Shreya Bhattacharya for technical assistance; Dr Monique Smeets for comments and discussion; SVI Flow Cytometry Facility (M Thomson and E Orlowski) for assistance with FACS analysis. This work was supported by grants from the Cancer Council of Victoria (to C.W. and E.B.); NHMRC Career Development Award (to C.W.); Zig Inge Foundation (to C.W.); Cure Cancer Australia Foundation (to E.B); 5point foundation (to E.B and C.W.); in part by the Victorian State Government Operational Infrastructure Support Program (to St. Vincent's Institute). C.W. is the Philip Desbrow Senior Research Fellow of the Leukaemia Foundation.