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Korean J Physiol Pharmacol 2018 Jan; 22(1): 43-51
Ye-Na Ha1,#, Hye Youn Sung1,#, San-Duk Yang2, Yun Ju Chae1, Woong Ju3,*, and Jung-Hyuck Ahn1,*
Epigenetic modification of α-N-acetylgalactosaminidase enhances cisplatin resistance in ovarian cancer
1Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 07985, 2Department of Biomedical Sciences, Seoul National University, College of Medicine, Seoul 03080, 3Department of Obstetrics and Gynecology, School of Medicine, Ewha Womans University Seoul 07985, Korea
Although cisplatin is one of the most effective antitumor drugs for ovarian cancer, the emergence of chemoresistance to cisplatin in over 80% of initially responsive patients is a major barrier to successful therapy. The precise mechanisms underlying the development of cisplatin resistance are not fully understood, but alteration of DNA methylation associated with aberrant gene silencing may play a role. To identify epigenetically regulated genes directly associated with ovarian cancer cisplatin resistance, we compared the expression and methylation profiles of cisplatin-sensitive and -resistant human ovarian cancer cell lines. We identified α-N-acetylgalactosaminidase (NAGA) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, NAGA was significantly down-regulated and hypermethylated at a promoter CpG site at position +251 relative to the transcriptional start site. Low NAGA expression in cisplatin-resistant cell lines was restored by treatment with a DNA demethylation agent, indicating transcriptional silencing by hyper-DNA methylation. Furthermore, overexpression of NAGA in cispla-tin-resistant lines induced cytotoxicity in response to cisplatin, whereas depletion of NAGA expression increased cisplatin chemoresistance, suggesting an essential role of NAGA in sensitizing ovarian cells to cisplatin. These findings indicate that NAGA acts as a cisplatin sensitizer and its gene silencing by hypermethylation confers resistance to cisplatin in ovarian cancer. Therefore, we suggest NAGA may be a promising potential therapeutic target for improvement of sensitivity to cisplatin in ovarian cancer.
Keyword : Cisplatin resistance, DNA methylation, Ovarian cancer, α-N-acetylgalactosaminidase