The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer.
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.
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Department of Biochemistry/UFRGS, Porto Alegre, Brazil.|CAPES Foundation, Ministry of Education of Brazil, Brasilia, Brazil.
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da Motta
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Ledaki
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Purshouse
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Haider
Department of Biochemistry/UFRGS, Porto Alegre, Brazil.
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De Bastiani
High Throughput Genomics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
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Baban
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Morotti
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Steers
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Wigfield
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Bridges
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Institute of Translational and Stratified Medicine, Plymouth University, Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
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Li
Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Oxford, UK.|Goethe University Frankfurt, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Campus Riedberg, Frankfurt, Germany.
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Knapp
Nuffield Department of Medicine, Target Discovery Institute (TDI), University of Oxford, Oxford, UK.
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Ebner
Department of Biochemistry/UFRGS, Porto Alegre, Brazil.
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Klamt
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
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Harris
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.|Cancer Biology, Division of Cancer and Stem Cells, The University of Nottingham, Nottingham, UK.
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McIntyre
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D000071231:Carbonic Anhydrase IX / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018874:Spheroids, Cellular; D059467:Transcriptome; D014230:Triazoles / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D023041:Xenograft Model Antitumor Assays
C561695:(+)-JQ1 compound; D001381:Azepines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D000071231:Carbonic Anhydrase IX