Page 126 - D. Cancer biology

[D. Cancer biology-79]

Aberrant hypomethylation mediated-Poly (ADP-Ribose)

polymerase family member 4 overexpression induces

cisplatin resistance of ovarian cancer

Jung-Hyuck Ahn¹

¹Biochemistry, College of Medicine, Ewha Womans University, Seoul 07804, Korea

Although cisplatin is one of the most effective antitumor drugs for ovarian cancer, the emergence of
chemoresistance to cisplatin is a major barrier to successful therapy. 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 PARP4 as one of the key candidate
genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, PARP4 was significantly upregulated

and hypomethylated at a specific promoter CpG site and further validated its DNA methylation-dependent
transcriptional regulation by treatment of demethylating agent. Furthermore, depletion of PARP4 in cisplatin-

resistant cells induced cytotoxicity in response to cisplatin. Finally, we analyzed human ovarian cancer patient
samples and showed DNA hypomethylation at a specific CpG site within PARP4 promoter in chemoresistant patients.

DNA methylation status at the specific promoter CpG site readily distinguished chemoresistant patients from
chemosensitive patients with high accuracy. Our findings suggest DNA methylation status at the PARP4 promoter

CpG site is a potential biomarker for predicting chemoresistance.