Cisplatin Resistance in Epstein–Barr-Virus-Associated Gastric Carcinoma Acquired through ATM Methylation

Cancers

Dong Sun Kim¹  Jong Gwang Kim²  Byung Woog Kang²  Wonhyeok Choi³  Hyosun Cho³  Sun Hee Lee⁴  Miyeon Cho⁴  Subin Cho⁴  Hyojeung Kang⁴  Su Jin Choi⁴  You Mie Lee⁵ 

[1] Department of Anatomy, School of Medicine, Kyungpook National University, Daegu 41944, Korea;Department of Oncology/Hematology, Cancer Research Institute, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41405, Korea;Duksung Innovative Drug Center, College of Pharmacy, Duksung Women’s University, Seoul 01369, Korea;Vessel-Organ Interaction Research Center, VOICE (MRC), Cancer Research Institute, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea;Vessel-Organ Interaction Research Center, VOICE (MRC), Department of Molecular Pathophysiology, College of Pharmacy, Kyungpook National University, Daegu 41566, Korea;

关键词: cisplatin;    5-Azacytidine;    DNA methylation;    Epstein–Barr virus;    DNMT3A;    ATM;   

DOI  :  10.3390/cancers13174252

来源: DOAJ

【 摘 要 】

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 DNMT3A gene, whereas shRNA-targeted removal of DNMT3A mRNA contributed to cisplatin-mediated EBV lytic reactivation. Moreover, the removal of DNMT3A mRNA upregulated the ATM gene through DNA demethylation on the ATM promoter. Furthermore, CRISPR/Cas9-targeted removal of the ATM 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.

【 授权许可】

Unknown