Identification of a novel PARP4 gene promoter CpG locus associated with cisplatin chemoresistance

Hye Youn Sung, Jihye Han, Yun Ju Chae, Woong Ju, Jihee Lee Kang, Ae Kyung Park, Jung Hyuck Ahn

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The protein family of poly (ADP-ribose) polymerases (PARPs) is comprised of multifunctional nuclear enzymes. Several PARP inhibitors have been developed as new anticancer drugs to combat resistance to chemotherapy. Herein, we characterized PARP4 mRNA expression profiles in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. PARP4 mRNA expression was significantly upregulated in cisplatin-resistant ovarian cancer cell lines, and this upregulation was associated with the hypomethylation of specific cytosine-phosphate-guanine (CpG) sites (cg18582260 and cg17117459) on its promoter. Reduced PARP4 expression was restored by treating cisplatin-sensitive cell lines with a demethylation agent, implicating the epigenetic regulation of PARP4 expression by promoter methylation. Depletion of PARP4 expression in cisplatin-resistant cell lines reduced cisplatin chemoresistance and promoted cisplatin-induced DNA fragmentation. The differential mRNA expression and DNA methylation status at specific PARP4 promoter CpG sites (cg18582260 and cg17117459) according to cisplatin responses, was further validated in primary ovarian tumor tissues. The results showed significantly increased PARP4 mRNA expressions and decreased DNA methylation levels at specific PARP4 promoter CpG sites (cg18582260 and cg17117459) in cisplatin-resistant patients. Additionally, the DNA methylation status at cg18582260 CpG sites in ovarian tumor tissues showed fairly clear discrimination between cisplatin-resistant patients and cisplatin-sensitive patients, with high accuracy (area under the curve = 0.86, P = 0.003845). Our findings suggest that the DNA methylation status of PARP4 at the specific promoter site (cg18582260) may be a useful diagnostic biomarker for predicting the response to cisplatin in ovarian cancer patients.

Original languageEnglish
Pages (from-to)347-352
Number of pages6
JournalBMB Reports
Volume56
Issue number6
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
© (2023), (The Biochemical Society of the Republic of Korea). All Rights Reserved.

Keywords

  • Biomarker
  • Cisplatin resistance
  • DNA methylation
  • Ovarian cancer
  • PARP4

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