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Involvement of HIF-1α in the Detection, Signaling, and Repair of DNA Double-Strand Breaks after Photon and Carbon-Ion Irradiation

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Cellular and Molecular Radiobiology Laboratory, Lyon-Sud Medical School, UMR CNRS5822/IP2I, Univ Lyon, Lyon 1 University, 69921 Oullins, France
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Department of Biochemistry and Molecular Biology, Lyon-Sud Hospital, Hospices Civils de Lyon, 69310 Pierre-Bénite, France
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Univ Lyon, Lyon 1 University, UMR CNRS5822/IP2I, 69100 Villeurbanne, France
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Department of Radiotherapy, Institute of Cancerology Lucien Neuwirth, 42270 Saint-Priest-en-Jarez, France
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Department of Radiation Effects Research, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Sonia Rocha and George Simos
Cancers 2021, 13(15), 3833; https://doi.org/10.3390/cancers13153833
Received: 1 July 2021 / Revised: 22 July 2021 / Accepted: 26 July 2021 / Published: 30 July 2021
(This article belongs to the Section Tumor Microenvironment)
Hypoxia-Inducible Factor 1α (HIF-1α), the main regulator of the oxygen homeostasis, promotes cancer cell survival through proliferation, angiogenesis, metastasis and radioresistance. Previously, our group demonstrated that silencing HIF-1α under hypoxia leads to a substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and carbon-ions, probably resulting from an accumulation of deleterious complex DNA damage. In this study, we aimed at determining the potential role of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, under hypoxia, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). Silencing HIF-1α under hypoxia led us to demonstrate the involvement of this transcriptional regulator in DSB repair in non-CSCS and CSC, thus highlighting its targeting together with radiation as a promising therapeutic strategy against radioresistant tumor cells in hypoxic niches.
Hypoxia-Inducible Factor 1α (HIF-1α), which promotes cancer cell survival, is the main regulator of oxygen homeostasis. Hypoxia combined with photon and carbon ion irradiation (C-ions) stabilizes HIF-1α. Silencing HIF-1α under hypoxia leads to substantial radiosensitization of Head-and-Neck Squamous Cell Carcinoma (HNSCC) cells after both photons and C-ions. Thus, this study aimed to clarify a potential involvement of HIF-1α in the detection, signaling, and repair of DNA Double-Strand-Breaks (DSBs) in response to both irradiations, in two HNSCC cell lines and their subpopulations of Cancer-Stem Cells (CSCs). After confirming the nucleoshuttling of HIF-1α in response to both exposure under hypoxia, we showed that silencing HIF-1α in non-CSCs and CSCs decreased the initiation of the DSB detection (P-ATM), and increased the residual phosphorylated H2AX (γH2AX) foci. While HIF-1α silencing did not modulate 53BP1 expression, P-DNA-PKcs (NHEJ-c) and RAD51 (HR) signals decreased. Altogether, our experiments demonstrate the involvement of HIF-1α in the detection and signaling of DSBs, but also in the main repair pathways (NHEJ-c and HR), without favoring one of them. Combining HIF-1α silencing with both types of radiation could therefore present a potential therapeutic benefit of targeting CSCs mostly present in tumor hypoxic niches. View Full-Text
Keywords: hypoxia-inducible factor 1; double-strand breaks; DNA repair; homologous recombination; non-homologous end joining pathway; irradiations; carbon ions; photons; hypoxia; cancer stem cells hypoxia-inducible factor 1; double-strand breaks; DNA repair; homologous recombination; non-homologous end joining pathway; irradiations; carbon ions; photons; hypoxia; cancer stem cells
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MDPI and ACS Style

Wozny, A.-S.; Gauthier, A.; Alphonse, G.; Malésys, C.; Varoclier, V.; Beuve, M.; Brichart-Vernos, D.; Magné, N.; Vial, N.; Ardail, D.; Nakajima, T.; Rodriguez-Lafrasse, C. Involvement of HIF-1α in the Detection, Signaling, and Repair of DNA Double-Strand Breaks after Photon and Carbon-Ion Irradiation. Cancers 2021, 13, 3833. https://doi.org/10.3390/cancers13153833

AMA Style

Wozny A-S, Gauthier A, Alphonse G, Malésys C, Varoclier V, Beuve M, Brichart-Vernos D, Magné N, Vial N, Ardail D, Nakajima T, Rodriguez-Lafrasse C. Involvement of HIF-1α in the Detection, Signaling, and Repair of DNA Double-Strand Breaks after Photon and Carbon-Ion Irradiation. Cancers. 2021; 13(15):3833. https://doi.org/10.3390/cancers13153833

Chicago/Turabian Style

Wozny, Anne-Sophie, Arnaud Gauthier, Gersende Alphonse, Céline Malésys, Virginie Varoclier, Michael Beuve, Delphine Brichart-Vernos, Nicolas Magné, Nicolas Vial, Dominique Ardail, Tetsuo Nakajima, and Claire Rodriguez-Lafrasse. 2021. "Involvement of HIF-1α in the Detection, Signaling, and Repair of DNA Double-Strand Breaks after Photon and Carbon-Ion Irradiation" Cancers 13, no. 15: 3833. https://doi.org/10.3390/cancers13153833

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