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.