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DNA methylation changes following DNA damage in prostate cancer cells

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Sutton, LP, Jeffreys, SA, Phillips, JL, Taberlay, PC ORCID: 0000-0002-5298-8730, Holloway, AF ORCID: 0000-0003-2213-1717, Ambrose, M ORCID: 0000-0002-8031-8240, Joo, J-HE, Young, Arabella, Berry, R ORCID: 0000-0001-7172-8830, Skala, M and Brettingham-Moore, KH ORCID: 0000-0002-4304-4586 2019 , 'DNA methylation changes following DNA damage in prostate cancer cells' , Epigenetics , pp. 1-14 , doi: 10.1080/15592294.2019.1629231.

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Abstract

Many cancer therapies operate by inducing double-strand breaks (DSBs) in cancer cells, however treatment-resistant cells rapidly initiate mechanisms to repair damage enabling survival. While the DNA repair mechanisms responsible for cancer cell survival following DNA damaging treatments are becoming better understood, less is known about the role of the epigenome in this process. Using prostate cancer cell lines with differing sensitivities to radiation treatment, we analysed the DNA methylation profiles prior to and following a single dose of radiotherapy (RT) using the Illumina Infinium HumanMethylation450 BeadChip platform. DSB formation and repair, in the absence and presence of the DNA hypomethylating agent, 5-azacytidine (5-AzaC), were also investigated using γH2A.X immunofluorescence staining. Here we demonstrate that DNA methylation is generally stable following a single dose of RT; however, a small number of CpG sites are stably altered up to 14 d following exposure. While the radioresistant and radiosensitive cells displayed distinct basal DNA methylation profiles, their susceptibility to DNA damage appeared similar demonstrating that basal DNA methylation has a limited influence on DSB induction at the regions examined. Recovery from DSB induction was also similar between these cells. Treatment with 5-AzaC did not sensitize resistant cells to DNA damage, but rather delayed recruitment of phosphorylated BRCA1 (S1423) and repair of DSBs. These results highlight that stable epigenetic changes are possible following a single dose of RT and may have significant clinical implications for cancer treatment involving recurrent or fractionated dosing regimens.

Item Type: Article
Authors/Creators:Sutton, LP and Jeffreys, SA and Phillips, JL and Taberlay, PC and Holloway, AF and Ambrose, M and Joo, J-HE and Young, Arabella and Berry, R and Skala, M and Brettingham-Moore, KH
Keywords: prostate cancer, DNA damage, DNA repair, DNA methylation, epigenetics, radiotherapy, treatment response, radiation resistance
Journal or Publication Title: Epigenetics
Publisher: Taylor & Francis Inc.
ISSN: 1559-2294
DOI / ID Number: 10.1080/15592294.2019.1629231
Copyright Information:

Copyright 2019 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/

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