Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

Esther Arnaiz; Ana Miar; Antonio Gregorio Dias Junior; Naveen Prasad; Ulrike Schulze; Dominic Waithe; James A Nathan; Jan Rehwinkel; Adrian L Harris

doi:10.3389/fonc.2021.779739

Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

Front Oncol. 2021 Nov 24:11:779739. doi: 10.3389/fonc.2021.779739. eCollection 2021.

Authors

Esther Arnaiz^{1

2}, Ana Miar^{1

3}, Antonio Gregorio Dias Junior⁴, Naveen Prasad³, Ulrike Schulze⁵, Dominic Waithe⁵, James A Nathan², Jan Rehwinkel⁴, Adrian L Harris¹

Affiliations

¹ Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
² Cambridge Institute for Therapeutic Immunology & Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge, United Kingdom.
³ Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, United Kingdom.
⁴ Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
⁵ Radcliffe Department of Medicine, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.

Abstract

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.

Keywords: IFN; cancer; dsRNA; hypoxia; mitochondria.

Abstract

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