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Cited by 41Cancer, Hypoxia, and MetabolismEffects of Radiation ExposureRadiation Therapy and Dosimetry

Activation of Hif1α by the Prolylhydroxylase Inhibitor Dimethyoxalyglycine Decreases Radiosensitivity

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Ayrapetov, Marina K., Xu, Chang, Sun, Yingli, Zhu, Kaya, Parmar, Kalindi, D'Andrea, Alan D., Price, Brendan D.·2011·PLoS ONE
DOI 10.1371/journal.pone.0026064PMC PMC3189247
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Abstract

Hypoxia inducible factor 1α (Hif1α) is a stress responsive transcription factor, which regulates the expression of genes required for adaption to hypoxia. Hif1α is normally hydroxylated by an oxygen-dependent prolylhydroxylase, leading to degradation and clearance of Hif1α from the cell. Under hypoxic conditions, the activity of the prolylhydroxylase is reduced and Hif1α accumulates. Hif1α is also constitutively expressed in tumor cells, where it is associated with resistance to ionizing radiation. Activation of the Hif1α transcriptional regulatory pathway may therefore function to protect normal cells from DNA damage caused by ionizing radiation. Here, we utilized the prolylhydroxylase inhibitor dimethyloxalylglycine (DMOG) to elevate Hif1α levels in mouse embryonic fibroblasts (MEFs) to determine if DMOG could function as a radioprotector. The results demonstrate that DMOG increased Hif1α protein levels and decreased the sensitivity of MEFs to ionizing radiation. Further, the ability of DMOG to function as a radioprotector required Hif1α, indicating a key role for Hif1α's transcriptional activity. DMOG also induced the Hif1α -dependent accumulation of several DNA damage response proteins, including CHD4 and MTA3 (sub-units of the NuRD deacetylase complex) and the Suv39h1 histone H3 methyltransferase. Depletion of Suv39h1, but not CHD4 or MTA3, reduced the ability of DMOG to protect cells from radiation damage, implicating increased histone H3 methylation in the radioprotection of cells. Finally, treatment of mice with DMOG prior to total body irradiation resulted in significant radioprotection of the mice, demonstrating the utility of DMOG and related prolylhydroxylase inhibitors to protect whole organisms from ionizing radiation. Activation of Hif1α through prolylhydroxylase inhibition therefore identifies a new pathway for the development of novel radiation protectors.

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Authors
Ayrapetov, M. K., Xu, C., Sun, Y., Zhu, K., Parmar, K., D'Andrea, A. D., & Price, B. D.
Affiliations
  • Harvard University (US)
  • Chinese Academy of Sciences (CN)
Corresponding author
  • Sun, Yingli
  • Parmar, Kalindi
  • Price, Brendan D.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-10-07
Volume
6
Issue
10
Pages
e26064
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0026064
PMC
PMC3189247
OpenAlex
W1970044001
Cited by
41
References
10
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 5 · 2013: 3 · 2012: 1
FWCI
0.98
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Public Health Service (U19A1067751)
  • National Cancer Institute (R01CA064585, R01CA093602, CA64585, CA93602)
  • National Institute of Allergy and Infectious Diseases
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
Keywords
HIF-1α, dimethyloxalylglycine, radiosensitivity, radiation protection, ionizing radiation, hypoxia, DNA damage response, histone H3 methylation, SUV39H1, CHD4, MTA3, NuRD complex, mouse embryonic fibroblasts, total body irradiation
MeSH terms
Amino Acids, Dicarboxylic, Animals, Autoantigens, Enzyme Inhibitors, Fibroblasts, Humans, Neoplasm Proteins, Procollagen-Proline Dioxygenase, Radiation Tolerance, Radiation-Protective Agents, RNA, Messenger, Up-Regulation, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Mi-2 Nucleosome Remodeling and Deacetylase Complex, HEK293 Cells

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