133257 - DNA methylation changes following DNA damage in prostate cancer cells.pdf (3.99 MB)
DNA methylation changes following DNA damage in prostate cancer cells
journal contributionposted on 2023-05-20, 04:30 authored by Laura SuttonLaura Sutton, Jeffreys, SA, Jessica Phillips, Phillippa TaberlayPhillippa Taberlay, Adele HollowayAdele Holloway, Mark AmbroseMark Ambrose, Joo, J-HE, Young, A, Rachael BerryRachael Berry, Skala, M, Kate Brettingham-MooreKate Brettingham-Moore
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.
Cancer Council of Tasmania
Department/SchoolTasmanian School of Medicine
PublisherTaylor & Francis Inc.
Place of publicationUnited States
Rights statementCopyright 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/