DNA methylation changes following DNA damage in prostate cancer cells
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2019-10-01
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| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2019.1629231 |
| _version_ | 1797678907882733568 |
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| author | Laura P. Sutton Sarah A. Jeffreys Jessica L. Phillips Phillippa C. Taberlay Adele F. Holloway Mark Ambrose Ji-Hoon E. Joo Arabella Young Rachael Berry Marketa Skala Kate H. Brettingham-Moore |
| author_facet | Laura P. Sutton Sarah A. Jeffreys Jessica L. Phillips Phillippa C. Taberlay Adele F. Holloway Mark Ambrose Ji-Hoon E. Joo Arabella Young Rachael Berry Marketa Skala Kate H. Brettingham-Moore |
| author_sort | Laura P. Sutton |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:06:46Z |
| format | Article |
| id | doaj.art-ad75c7e39ad14f7f8858b1600d8512c4 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:46Z |
| publishDate | 2019-10-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-ad75c7e39ad14f7f8858b1600d8512c42023-09-21T13:09:22ZengTaylor & Francis GroupEpigenetics1559-22941559-23082019-10-011410989100210.1080/15592294.2019.16292311629231DNA methylation changes following DNA damage in prostate cancer cellsLaura P. Sutton0Sarah A. Jeffreys1Jessica L. Phillips2Phillippa C. Taberlay3Adele F. Holloway4Mark Ambrose5Ji-Hoon E. Joo6Arabella Young7Rachael Berry8Marketa Skala9Kate H. Brettingham-Moore10University of TasmaniaUniversity of TasmaniaUniversity of TasmaniaUniversity of TasmaniaUniversity of TasmaniaUniversity of TasmaniaThe University of MelbourneUniversity of TasmaniaUniversity of TasmaniaRoyal Hobart HospitalUniversity of TasmaniaMany 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.http://dx.doi.org/10.1080/15592294.2019.1629231prostate cancerdna damagedna repairdna methylationepigeneticsradiotherapytreatment responseradiation resistance |
| spellingShingle | Laura P. Sutton Sarah A. Jeffreys Jessica L. Phillips Phillippa C. Taberlay Adele F. Holloway Mark Ambrose Ji-Hoon E. Joo Arabella Young Rachael Berry Marketa Skala Kate H. Brettingham-Moore DNA methylation changes following DNA damage in prostate cancer cells Epigenetics prostate cancer dna damage dna repair dna methylation epigenetics radiotherapy treatment response radiation resistance |
| title | DNA methylation changes following DNA damage in prostate cancer cells |
| title_full | DNA methylation changes following DNA damage in prostate cancer cells |
| title_fullStr | DNA methylation changes following DNA damage in prostate cancer cells |
| title_full_unstemmed | DNA methylation changes following DNA damage in prostate cancer cells |
| title_short | DNA methylation changes following DNA damage in prostate cancer cells |
| title_sort | dna methylation changes following dna damage in prostate cancer cells |
| topic | prostate cancer dna damage dna repair dna methylation epigenetics radiotherapy treatment response radiation resistance |
| url | http://dx.doi.org/10.1080/15592294.2019.1629231 |
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