The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer

da Motta, L L; Ledaki, I; Purshouse, K; Haider, S; de Bastiani, M; Baban, D; Morotti, M; Steers, G; Wigfield, S; Bridges, E; Li, J-L; Knapp, S; Ebner, D; Klamt, F; Harris, A L; McIntyre, A

Abstract

The availability of bromodomain and extra-terminal inhibitors (BETi) has enabled translational epigenetic studies in cancer. BET proteins regulate transcription by selectively recognizing acetylated lysine residues on chromatin. BETi compete with this process leading to both downregulation and upregulation of gene expression. Hypoxia enables progression of triple negative breast cancer (TNBC), the most aggressive form of breast cancer, partly by driving metabolic adaptation, angiogenesis and metastasis through upregulation of hypoxia-regulated genes (for example, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A). Responses to hypoxia can be mediated epigenetically, thus we investigated whether BETi JQ1 could impair the TNBC response induced by hypoxia and exert anti-tumour effects. JQ1 significantly modulated 44% of hypoxia-induced genes, of which two-thirds were downregulated including CA9 and VEGF-A. JQ1 prevented HIF binding to the hypoxia response element in CA9 promoter, but did not alter HIF expression or activity, suggesting some HIF targets are BET-dependent. JQ1 reduced TNBC growth in vitro and in vivo and inhibited xenograft vascularization. These findings identify that BETi dually targets angiogenesis and the hypoxic response, an effective combination at reducing tumour growth in preclinical studies.

Citation

da Motta, L. L., Ledaki, I., Purshouse, K., Haider, S., de Bastiani, M., Baban, D., Morotti, M., Steers, G., Wigfield, S., Bridges, E., Li, J.-L., Knapp, S., Ebner, D., Klamt, F., Harris, A. L., & McIntyre, A. (2017). The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene, 36, 122-132. https://doi.org/10.1038/onc.2016.184

• Journal Article Type: Article
• Acceptance Date: Apr 15, 2016
• Online Publication Date: Jun 13, 2016
• Publication Date: Jan 5, 2017
• Deposit Date: Jul 5, 2018
• Publicly Available Date: Jul 30, 2020
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 36
• Pages: 122-132
• DOI: https://doi.org/10.1038/onc.2016.184
• Public URL: https://nottingham-repository.worktribe.com/output/1110898
• Publisher URL: https://www.nature.com/articles/onc2016184
• Related Public URLs: https://www.nature.com/articles/onc2016184