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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Identification of a novel PARP4 gene promoter CpG locus associated with cisplatin chemoresistance

  • Hye Youn Sung (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Jihye Han (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Yun Ju Chae (Department of Biochemistry, College of Medicine, Ewha Womans University) ;
  • Woong Ju (Department of Obstetrics and Gynecology, College of Medicine, Ewha Womans University) ;
  • Jihee Lee Kang (Department of Physiology, College of Medicine, Ewha Womans University) ;
  • Ae Kyung Park (Department of Pharmacy, School of Pharmacy, Jeonbuk National University) ;
  • Jung-Hyuck Ahn (Department of Biochemistry, College of Medicine, Ewha Womans University)
  • Received : 2022.11.30
  • Accepted : 2023.04.01
  • Published : 2023.06.30
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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.

Keywords

Acknowledgement

The research resources (tumor tissues from patients with ovarian cancer) were provided by Korea Gynecologic Cancer Bank (KGCB) of the Infrastructure Project for Basic Science of the Ministry of Education, Science, and Technology (MEST), Korea. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1D1A1B070 43451, NRF-2022R1I1A1A01068767, NRF- 2020R1I1A3073845), and the Korean government (MSIT) (NRF-2020R1A5A2019210). The present study was also supported by RP-Grant 2021 of Ewha Womans University.

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