Hye Youn Sung

MBNL2 enhances cisplatin resistance by regulating apoptosis in ovarian cancer cells

Although cisplatin is an effective anticancer agent for treating ovarian cancer, it encounters significant resistance. A full understanding of the mechanisms behind cisplatin resistance has not been achieved. This study identifies MBNL2 as a crucial regulator of cellular responses to cisplatin, examining variations in gene expression and methylation profiles between cisplatinsensitive and -resistant ovarian cancer cells. Cells resistant to cisplatin exhibited increased MBNL2 mRNA expression and significant demethylation at promoter CpG sites. Treating ovarian cancer cell lines with a DNA demethylating agent significantly raised MBNL2 mRNA expression, indicating that epigenetic mechanisms involving DNA methylation control MBNL2 expression. Modulating MBNL2 levels altered the response to cisplatin through survival pathways that shield cells from cisplatin-induced apoptosis. Overexpressing MBNL2 enhanced resistance, while its depletion heightened cisplatin sensitivity. Furthermore, MBNL2 mRNA levels differed among patients based on their response to platinum-based chemotherapeutics. Patients resistant to these drugs had higher MBNL2 mRNA levels, effectively distinguishing them from those who were sensitive (AUC = 0.89, P = 0.0308). A meta-analysis of seventeen datasets confirmed that lower MBNL2 expression levels are associated with a better chemotherapy response and longer relapse-free survival. Conversely, higher MBNL2 expression levels correlated with increased recurrence rates and reduced survival. Thus, MBNL2 may serve as a promising prognostic and therapeutic target for overcoming cisplatin resistance. [BMB Reports 2025; 58(5): 224-231].

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

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. [BMB Reports 2023; 56(6): 347-352].