DNA Methylation Repels Binding of HIF Transcription Factors to Maintain Tumour Immunotolerance

This abstract was selected by our Scientific Committee to pitch on the programme in the R2B session (PM).

Tumour cells vary considerably in their response to hypoxia, but the mechanisms underlying these differential responses are largely unknown. Here, we report that hypoxia-inducible factors (HIFs) are directly repelled by methylation of CpG dinucleotides in their binding site. This instructive role of DNA methylation is caused by steric hindrance of 5-methylcytosine in the HIF binding pocket. Our data suggest a model wherein tumour- and cell-type-specific methylation landscapes are laid-down by the differential expression and binding of transcription factors under normoxia, subsequently controlling the hypoxia response through methylation at HIF binding sites. Upon DNA methylation interference, either genetically or pharmacologically, ectopic HIF binding sites in retrotransposons, which are normally masked by methylation, become exposed to HIFs and retrotransposon expression induced upon hypoxia. In line with retrotransposon expression in tumours being immunogenic, we observe reduced DNA methylation and high expression of retrotransposons in tumours with high immune checkpoint expression, but not in tumours with low immune checkpoint expression, where tumour immunotolerance would otherwise be compromised. The latter is confirmed in a low-immunogenic mouse tumour model, in which DNA demethylation HIF-dependently upregulates retrotransposons, causing immune activation and reduced tumour growth. Overall, this suggests novel treatment strategies involving DNA methylation inhibitors specifically for hypoxic tumours.

Authors

LAURIEN VAN DYCK (1,2), FLORA D’ANNA (1,2), HUI ZHAO (1,2), REBECCA V. BERRENS (3,4), PAWEL BIENIASZ-KRZYWIEC (1,5), VIKAS CHANDRA (12), LUC SCHOONJANS (1,17,18), JASON MATTHEWS (11), LIESBETH MINNOYE (1,2), JUNBIN QIAN (1,2), RICARDO AMORIM (1,5), SEPIDEH KHORASANIZADEH (12), MARIE DE BORRE (14), SAVVAS N. SAVVIDES (6,7), CELESTE SIMON (15,16), WOLF REIK (3,8,9,10), PETER CARMELIET (1,17,18), FRAYDOON RASTINEJAD (12, 13), MASSIMILIANO MAZZONE (1,5), BERNARD THIENPONT (1,2,14), DIETHER LAMBRECHTS (1,2)

Organisations

Center for Cancer Biology, VIB, 3000 Leuven, Belgium (1), Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium (2), Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK (3), University of Cambridge, The Old Schools, Trinity Lane Cambridge, CB2 1TN, UK (4), Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium (5), Unit for Structural Biology, Department of Biochemistry and Microbiology, Ghent University, 9052 Ghent, Belgium (6), VIB Center for Inflammation Research, 9052 Ghent, Belgium (7), Centre for Trophoblast Research, University of Cambridge, Cambridge, CB2 3EG, UK (8), Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK (9), Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3EG, UK (10), Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway (11), Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL, 32827, USA (12), Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, 3000 Leuven, Belgium (13), Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium (14), Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (15), Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA (16), State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China (17), Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, 3000 Leuven, Belgium (18)

Presenting author

Laurien Van Dyck, PhD student, Center for Cancer Biology, VIB, 3000 Leuven, Belgium (1), Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium (2)
laurien.vandyck@kuleuven.vib.be
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