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

Anne-Sophie Wozny (1, 2) , Arnaud Gauthier (1, 2) , Gersende Alphonse (1, 2) , Céline Malésys (1) , Virginie Varoclier (1) , Michael Beuve (1) , Delphine Brichart-Vernos (1) , Nicolas Magné (1, 3) , Nicolas Vial (1, 3) , Dominique Ardail (1) , Tetsuo Nakajima (4) , Claire Rodriguez-Lafrasse (1, 2)

1 IP2I Lyon - Institut de Physique des 2 Infinis de Lyon
2 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
3 Institut de Cancérologie Lucien Neuwirth
4 Department of Radiation Effects Research [Chiba, Japon]

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.

Mots clés: DNA repair; cancer stem cells; carbon ions; double-strand breaks; homologous recombination; hypoxia; hypoxia-inducible factor 1; irradiations; non-homologous end joining pathway; photons

Domaines: Cancer

Anne-Sophie Wozny, Arnaud Gauthier, Gersende Alphonse, Céline Malésys, Virginie Varoclier, et al.. 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), pp.3833. ⟨10.3390/cancers13153833⟩. ⟨hal-03326508⟩