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Epigenetic modification of α-N-acetylgalactosaminidase enhances cisplatin resistance in ovarian cancer

Epigenetic modification of α-N-acetylgalactosaminidase enhances cisplatin resistance in ovarian cancer

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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-<em>N</em>-acetylgalactosaminidase (<i>NAGA</i>) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, <i>NAGA</i> was significantly down-regulated and hypermethylated at a promoter CpG site at position +251 relative to the transcriptional start site. Low <i>NAGA</i> 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 <i>NAGA</i> in cispla-tin-resistant lines induced cytotoxicity in response to cisplatin, whereas depletion of <i>NAGA</i> expression increased cisplatin chemoresistance, suggesting an essential role of <i>NAGA</i> 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 <i>NAGA</i> may be a promising potential therapeutic target for improvement of sensitivity to cisplatin in ovarian cancer.

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