Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription.
Dias Junior, Antonio Gregorio
Harris, Adrian L
Frontiers Media SA
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Arnaiz, E., Miar, A., Dias Junior, A. G., Prasad, N., Schulze, U., Waithe, D., Nathan, J., et al. (2021). Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription.. Front Oncol, 11 779739. https://doi.org/10.3389/fonc.2021.779739
Hypoxia is a common phenomenon in solid tumours strongly linked to the hallmarks of cancer. Hypoxia promotes local immunosuppression and downregulates type I interferon (IFN) expression and signalling, which contribute to the success of many cancer therapies. Double-stranded RNA (dsRNA), transiently generated during mitochondrial transcription, endogenously activates the type I IFN pathway. We report the effects of hypoxia on the generation of mitochondrial dsRNA (mtdsRNA) in breast cancer. We found a significant decrease in dsRNA production in different cell lines under hypoxia. This effect was HIF1α/2α-independent. mtdsRNA was responsible for induction of type I IFN and significantly decreased after hypoxia. Mitochondrially encoded gene expression was downregulated and mtdsRNA bound by the dsRNA-specific J2 antibody was decreased during hypoxia. These findings reveal a new mechanism of hypoxia-induced immunosuppression that could be targeted by hypoxia-activated therapies.
IFN, cancer, dsRNA, hypoxia, mitochondria
Wellcome Trust (215477/Z/19/Z)
External DOI: https://doi.org/10.3389/fonc.2021.779739
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333754
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/