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

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-acetylgalactosaminidase () as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, was significantly downregulated and hypermethylated at a promoter CpG site at position +251 relative to the transcriptional start site. Low 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 in cisplatin-resistant lines induced cytotoxicity in response to cisplatin, whereas depletion of expression increased cisplatin chemoresistance, suggesting an essential role of in sensitizing ovarian cells to cisplatin. These findings indicate that acts as a cisplatin sensitizer and its gene silencing by hypermethylation confers resistance to cisplatin in ovarian cancer. Therefore, we suggest may be a promising potential therapeutic target for improvement of sensitivity to cisplatin in ovarian cancer.