Radiation-induced epigenetic DNA methylation modification of radiation-response pathways

Antwih, Deborah A.; Gabbara, Kristina M.; Lancaster, Wayne D.; Ruden, Douglas M.; Zielske, Steven P.

doi:10.4161/epi.25498

Cited by 107 publications

(82 citation statements)

References 20 publications

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“…Aberrant DNA methylation has been previously reported in cellular non-response to ionizing radiation, particularly for genes involved in cell cycle control, DNA repair, and apoptosis [18]. In this regard, genes significantly enriched in the corresponding biological processes (purine nucleoside metabolic process and DNA metabolic process), based on our gene ontology analysis, were further screened.…”

Section: Resultsmentioning

confidence: 99%

DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study

et al. 2014

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Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using a methylation microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation, H3K27me3 and overexpression of methyltransferase EZH2 in OML1-R cells. Epigenetic interventions or depletion of EZH2 restored FHIT expression. Ectopic expression of FHIT inhibited tumor growth in both in vitro and in vivo models, while also resensitizing radioresistant cancer cells to irradiation, by restoring Chk2 phosphorylation and G2/M arrest. Clinically, promoter hypermethylation of FHIT inversely correlated with its expression and independently predicted both locoregional control and overall survival in 40 match-paired oral cancer patient samples. Further in vivo therapeutic experiments confirmed that inhibition of DNA methylation significantly resensitized radioresistant oral cancer cell xenograft tumors. These results show that epigenetic silencing of FHIT contributes partially to radioresistance and predicts clinical outcomes in irradiated oral cancer. The radiosensitizing effect of epigenetic interventions warrants further clinical investigation.

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Section: Resultsmentioning

confidence: 99%

DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study

et al. 2014

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“…Acute cellular stress has been shown to alter DNA methylation patterns at genes involved in stress response [38]. Gene-specific examinations of promoter regions and gene-bodies of 22 genes involved in stress and toxicity pathways including DNA damage, hypoxia signaling and growth arrest, did not reveal any change in the DNA methylation pattern over time.…”

Section: Discussionmentioning

confidence: 99%

The Genome-Wide DNA Methylation Profile of Peripheral Blood Is Not Systematically Changed by Short-Time Storage at Room Temperature

et al. 2017

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Abstract:Background: Epigenetic epidemiology has proven an important research discipline in the delineation of diseases of complex etiology. The approach, in such studies, is often to use bio-banked clinical material, however, many such samples were collected for purposes other than epigenetic studies and, thus, potentially not processed and stored appropriately. The Danish National Birth Cohort (DNBC) includes more than 100,000 peripheral and umbilical cord blood samples shipped from maternity wards by ordinary mail in EDTA tubes. While this and other similar cohorts hold great promises for DNA methylation studies the potential systematic changes prompted by storage at ambient temperatures have never been assessed on a genome-wide level. Methods and Results: In this study, matched EDTA whole blood samples were stored up to three days at room temperature prior to DNA extraction and methylated DNA immunoprecipitation coupled with deep sequencing (MeDIP-seq). We established that the quality of the MeDIP-seq libraries was high and comparable across samples; and that the methylation profiles did not change systematically during the short-time storage at room temperature. Conclusion: The global DNA methylation profile is stable in whole blood samples stored for up to three days at room temperature in EDTA tubes making genome-wide methylation studies on such material feasible.

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“…The genetic alterations induced by RT have been studied extensively. However the epigenetic alterations induced by RT have been left out even though these modifications can potentially lead to the change in transcriptional activity [35]. Halvorsen et al have demonstrated that DNA methylation levels of genes in the immune system pathways are significantly altered after irradiation in breast cancer [36].…”

Section: Potential Mechanisms Of Radiotherapy Combined With Immunothementioning

confidence: 99%

Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges

et al. 2015

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Radiation-induced epigenetic DNA methylation modification of radiation-response pathways

Cited by 107 publications

References 20 publications

DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study

DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study

The Genome-Wide DNA Methylation Profile of Peripheral Blood Is Not Systematically Changed by Short-Time Storage at Room Temperature

Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges

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