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

Abstract

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-Nacetylgalactosaminidase (NAGA) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, NAGA was significantly downregulated 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 cisplatin-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.

DNA methylation is associated with inhaled corticosteroid response in persistent childhood asthmatics

“…Our findings demonstrate its potential to identify treatment sensitivity in asthmatics. Epigenetic therapeutics that selectively target DNA methylation have been shown to increase the effectiveness of existing treatments in the field of cancer biology, and these therapeutics may have applications in other fields and diseases, including asthma . Further research into the identified DNA methylation marks may lead to the discovery of epigenetically mediated pathways of drug resistance and novel epigenetic therapeutics to increase sensitivity to ICS treatment.…”

“…Epigenetics can play a role in drug sensitivity and resistance . DNA methylation is an epigenetic mechanism that regulates both the activation and silencing of DNA transcription.…”

“…3,4 Epigenetics can play a role in drug sensitivity and resistance. [5][6][7][8][9][10] DNA methylation is an epigenetic mechanism that regulates both the activation and silencing of DNA transcription. Although DNA methylation has been implicated as a modifier of both asthma susceptibility and severity, the role of DNA methylation as a modifier of ICS treatment response in asthma has not been studied.…”

Epigenetic therapy can inhibit growth of ovarian cancer cells and reverse chemoresistant properties acquired from metastatic omentum

“…Over the last decade, the study of epigenetics in ovarian cancer has gained tremendous attention . Epigenetic modifications like DNA methylation and histone deacetylation lead to cancer progression, metastases, and an increase in chemoresistance in various cancers including ovarian cancer . Unlike genetic mutations that cannot be altered, epigenetically‐induced alterations are hopeful targets and their knowledge has led to the advent of histone deacetylase inhibitors (HDACis) and DNA hypomethylating agents (HMAs) …”

“…3 Epigenetic modifications like DNA methylation and histone deacetylation lead to cancer progression, metastases, and an increase in chemoresistance in various cancers including ovarian cancer. [4][5][6] Unlike genetic mutations that cannot be altered, epigenetically-induced alterations are hopeful targets and their knowledge has led to the advent of histone deacetylase inhibitors (HDACis) and DNA hypomethylating agents (HMAs). [7][8][9] Recently, there has been a great interest in understanding aberrant epigenetic events affecting not only the tumor but also its associated microenvironment.…”