Identification of a novel PARP4 gene promoter CpG locus associated with cisplatin chemoresistance
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The protein family of poly (ADP-ribose) polymerases (PARPs) iscomprised of multifunctional nuclear enzymes. Several PARPinhibitors have been developed as new anticancer drugs tocombat resistance to chemotherapy. Herein, we characterizedPARP4 mRNA expression profiles in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. PARP4 mRNA expressionwas significantly upregulated in cisplatin-resistant ovariancancer cell lines, and this upregulation was associated with thehypomethylation of specific cytosine-phosphate-guanine (CpG)sites (cg18582260 and cg17117459) on its promoter. ReducedPARP4 expression was restored by treating cisplatin-sensitive celllines with a demethylation agent, implicating the epigenetic regulationof PARP4 expression by promoter methylation. Depletionof PARP4 expression in cisplatin-resistant cell lines reducedcisplatin chemoresistance and promoted cisplatin-induced DNAfragmentation. The differential mRNA expression and DNA methylationstatus at specific PARP4 promoter CpG sites (cg18582260and cg17117459) according to cisplatin responses, was furthervalidated in primary ovarian tumor tissues. The results showedsignificantly increased PARP4 mRNA expressions and decreasedDNA methylation levels at specific PARP4 promoter CpG sites(cg18582260 and cg17117459) in cisplatin-resistant patients. Additionally, the DNA methylation status at cg18582260 CpGsites in ovarian tumor tissues showed fairly clear discriminationbetween 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 PARP4at the specific promoter site (cg18582260) may be a useful diagnosticbiomarker for predicting the response to cisplatin in ovariancancer patients.
Abstract
The protein family of poly (ADP-ribose) polymerases (PARPs) iscomprised of multifunctional nuclear enzymes. Several PARPinhibitors have been developed as new anticancer drugs tocombat resistance to chemotherapy. Herein, we characterizedPARP4 mRNA expression profiles in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines. PARP4 mRNA expressionwas significantly upregulated in cisplatin-resistant ovariancancer cell lines, and this upregulation was associated with thehypomethylation of specific cytosine-phosphate-guanine (CpG)sites (cg18582260 and cg17117459) on its promoter. ReducedPARP4 expression was restored by treating cisplatin-sensitive celllines with a demethylation agent, implicating the epigenetic regulationof PARP4 expression by promoter methylation. Depletionof PARP4 expression in cisplatin-resistant cell lines reducedcisplatin chemoresistance and promoted cisplatin-induced DNAfragmentation. The differential mRNA expression and DNA methylationstatus at specific PARP4 promoter CpG sites (cg18582260and cg17117459) according to cisplatin responses, was furthervalidated in primary ovarian tumor tissues. The results showedsignificantly increased PARP4 mRNA expressions and decreasedDNA methylation levels at specific PARP4 promoter CpG sites(cg18582260 and cg17117459) in cisplatin-resistant patients. Additionally, the DNA methylation status at cg18582260 CpGsites in ovarian tumor tissues showed fairly clear discriminationbetween 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 PARP4at the specific promoter site (cg18582260) may be a useful diagnosticbiomarker for predicting the response to cisplatin in ovariancancer patients.
참고문헌 (20)
- Yang L, "Exploring cisplatin resistance in ovarian cancer through integrated bioinformatics approach and overcoming chemoresistance with sanguinarine", Am J Transl Res, 12, pp.923~ (2020)
- Agarwal R, "Ovarian cancer : strategies for overcoming resistance to chemotherapy", Nat Rev Cancer, 3, pp.502~516 (2003)
- Makovec T, "Cisplatin and beyond : molecular mechanisms of action and drug resistance development in cancer chemotherapy", Radiol Oncol, 53, pp.148~158 (2019)
- Tapia G, "Molecular mechanisms of platinum resistance in ovarian cancer; in Ovarian cancera clinical and translational update" (2013), IntechOpen
- Chang X, "Identification of hypermethylated genes associated with cisplatin resistance in human cancers", Cancer Res, 70, pp.2870~2879 (2010)
- Bai P, "Biology of poly(ADP-ribose)polymerases : the factotums of cell maintenance", Mol Cell, 58, pp.947~958 (2015)
- Gibson BA, "New insights into the molecular and cellular functions of poly(ADP-ribose)and PARPs", Nat Rev Mol Cell Biol, 13, pp.411~424 (2012)
- Caldecott KW, "XRCC1 polypeptide interacts with DNA polymerase β and possibly poly(ADP-ribose)polymerase, and DNA ligase III is a novel molecular ‘nick-sensor’ in vitro", Nucleic Acids Res, 24, pp.4387~4394 (1996)
- Flohr C, "Poly(ADP-ribosyl)ation accelerates DNA repair in a pathway dependent on Cockayne syndrome B protein", Nucleic Acids Res, 31, pp.5332~5337 (2003)
- Mangerich A, "How to kill tumor cells with inhibitors of poly(ADP-ribosyl)ation", Int J Cancer, 128, pp.251~265 (2011)
- Ünlü A, "Investigation of the threedimensional structure and interaction mechanism of poly(ADP-ribose)polymerase 4", Biotechnol Biotec Eq, 34, pp.191~202 (2020)
- Siva AC, "Upregulation of vaults may be necessary but not sufficient for multidrug resistance", Int J Cancer, 92, pp.195~202 (2001)
- Berger W, "Overexpression of the human major vault protein in astrocytic brain tumor cells", Int J Cancer, 94, pp.377~382 (2001)
- 하예나, "Epigenetic modification of α-N-acetylgalactosaminidase enhances cisplatin resistance in ovarian cancer", The Korean Journal of Physiology & Pharmacology, 22(1), pp.43~51 (2018), 대한약리학회[DOI]
- Mora Y, "Resistance to platinum-based cancer drugs : a special focus on epigenetic mechanisms", Pharmacogenomics, 22, pp.777~790 (2021)
- van Zon A, "The vault complex", Cell Mol Life Sci, 60, pp.1828~1837 (2003)
- Raval-Fernandes S, "Increased susceptibility of vault poly(ADP-ribose)polymerase-deficient mice to carcinogen-induced tumorigenesis", Cancer Res, 65, pp.8846~8852 (2005)
- Szaflarski W, "Expression profiles of vault components MVP, TEP1 and vPARP and their correlation to other multidrug resistance proteins in ovarian cancer", Int J Oncol, 43, pp.513~520 (2013)
- Wu H, "Single‑cell intratumoral stemness analysis reveals the involvement of cell cycle and DNA damage repair in two different types of esophageal cancer", Oncol Rep, 41, pp.3201~3208 (2019)
- Kim NH, "Aberrant DNA methylation in the IFITM1 promoter enhances the metastatic phenotype in an intraperitoneal xenograft model of human ovarian cancer", Oncol Rep, 31, pp.2139~2146 (2014)