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

Abstract

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.

All‐In‐One Biomimetic Nanoplatform Based on Hollow Polydopamine Nanoparticles for Synergistically Enhanced Radiotherapy of Colon Cancer

“…[70,71] Hypoxia combined with IR stabilizes HIF-1α to inhibit the proliferation of tumor cells. [72] It is one of the reasons radiotherapy can be the most important therapeutic strategy for cancer treatment. However, IR cannot reduce the expression of HIF-1α and hypoxia is the leading cause of radiation resistance.…”

The ‘stealth-bomber’ paradigm for deciphering the tumour response to carbon-ion irradiation

“…Furthermore, supporting the lack of oxygen effect after C-ions, the same rejoining kinetics of DSBs were reported in oxic and hypoxic conditions after exposure. This is in favour of the same DSBs produced in both conditions but with modification of the contributions of the DNA repair mechanisms over time [ 55 , 56 ]. However, compared with photons, the repair time was longer after C-ions with more unrepaired damage, and whatever the oxygen concentration, these results support the ‘bomber’ effect of C-ions.…”

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

“…The authors indicated a possible link to the chromosomal instability status of cells and the possible absence of p53 and CHK2 activation (phosphorylation) but did not check effects on mitochondria. Interestingly, Wozny et al, showed that under hypoxia, silencing of HIF-1α that is translocating to the nucleus significantly radiosensitizes HNSCC and cancer stem cell subpopulations to photons and C-ion exposures because of decreased DSB detection by the ATM protein and decreased DSB repair by HR and NHEJ [ 288 ].…”