Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation
Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the ge...
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MDPI AG
2021-08-01
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| Online Access: | https://www.mdpi.com/2072-6694/13/17/4252 |
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| author | Sun Hee Lee Su Jin Choi Wonhyeok Choi Subin Cho Miyeon Cho Dong Sun Kim Byung Woog Kang Jong Gwang Kim You Mie Lee Hyosun Cho Hyojeung Kang |
| author_facet | Sun Hee Lee Su Jin Choi Wonhyeok Choi Subin Cho Miyeon Cho Dong Sun Kim Byung Woog Kang Jong Gwang Kim You Mie Lee Hyosun Cho Hyojeung Kang |
| author_sort | Sun Hee Lee |
| collection | DOAJ |
| description | Epstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the <i>DNMT3A</i> gene, whereas shRNA-targeted removal of <i>DNMT3A</i> mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of <i>DNMT3A</i> mRNA upregulated the <i>ATM</i> gene through DNA demethylation on the <i>ATM</i> promoter. Furthermore, CRISPR/Cas9-targeted removal of the <i>ATM</i> gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC. |
| first_indexed | 2024-03-10T08:15:54Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T08:15:54Z |
| publishDate | 2021-08-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b1a633d79d524a689771982618750f672023-11-22T10:24:26ZengMDPI AGCancers2072-66942021-08-011317425210.3390/cancers13174252Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> MethylationSun Hee Lee0Su Jin Choi1Wonhyeok Choi2Subin Cho3Miyeon Cho4Dong Sun Kim5Byung Woog Kang6Jong Gwang Kim7You Mie Lee8Hyosun Cho9Hyojeung Kang10Vessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaVessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaDuksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul 01369, KoreaVessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaVessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaDepartment of Anatomy, School of Medicine, Kyungpook National University, Daegu 41944, KoreaDepartment of Oncology/Hematology, Cancer Research Institute, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41405, KoreaDepartment of Oncology/Hematology, Cancer Research Institute, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41405, KoreaVessel-Organ Interaction Research Center, VOICE (MRC), Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaDuksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul 01369, KoreaVessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, KoreaEpstein–Barr-virus-associated gastric carcinoma (EBVaGC), first reported in 1992, currently accounts for 10% of all gastric carcinoma worldwide. EBVaGC has unique DNA hypermethylation phenotypes that allow for higher proportions of DNA methylation than any other gastric cancer. CpG islands in the gene promoter region are one of the major regions in which DNA methylation controls gene transcription. Despite cisplatin-based chemotherapy being one of the standard treatment regimens for advanced gastric cancer, including EBVaGC, cisplatin alone or in combination with 5-fluorouracil has been limited by its less potent anticancer activity and the occurrence of cisplatin resistance. Accordingly, the current study evaluated the anticancer activities of a combination of cisplatin and 5-Azacytidine (5-AZA) against EBVaGC. Our findings showed that cisplatin upregulated the <i>DNMT3A</i> gene, whereas shRNA-targeted removal of <i>DNMT3A</i> mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of <i>DNMT3A</i> mRNA upregulated the <i>ATM</i> gene through DNA demethylation on the <i>ATM</i> promoter. Furthermore, CRISPR/Cas9-targeted removal of the <i>ATM</i> gene resulted in significantly reduced cell susceptibility and EBV lytic reactivation by a combination of cisplatin and DNMT3A inhibitor 5-AZA. Finally, 5-AZA exhibited a synergistic effect with cisplatin in anti-EBV and anti-EBVaGC activities by increasing drug susceptibility and EBV lytic reactivation. The aforementioned results suggest that cisplatin combined with DNA methylation inhibitors could be a novel therapeutic approach for EBVaGC.https://www.mdpi.com/2072-6694/13/17/4252cisplatin5-AzacytidineDNA methylationEpstein–Barr virusDNMT3AATM |
| spellingShingle | Sun Hee Lee Su Jin Choi Wonhyeok Choi Subin Cho Miyeon Cho Dong Sun Kim Byung Woog Kang Jong Gwang Kim You Mie Lee Hyosun Cho Hyojeung Kang Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation Cancers cisplatin 5-Azacytidine DNA methylation Epstein–Barr virus DNMT3A ATM |
| title | Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation |
| title_full | Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation |
| title_fullStr | Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation |
| title_full_unstemmed | Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation |
| title_short | Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through <i>ATM</i> Methylation |
| title_sort | cisplatin resistance in epstein barr virus associated gastric carcinoma acquired through i atm i methylation |
| topic | cisplatin 5-Azacytidine DNA methylation Epstein–Barr virus DNMT3A ATM |
| url | https://www.mdpi.com/2072-6694/13/17/4252 |
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