Abstract B091: Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer

Abstract

Abstract Ovarian cancer is the second most commonly diagnosed gynecological cancer and has the highest mortality rate of all gynecological cancers worldwide. 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 Muscleblind Like Splicing Regulator 2 (MBNL2) as one of the key candidate genes for cisplatin drug response. Interestingly, in cisplatin-resistant cell lines, MBNL2 mRNA expression was significantly upregulated, and the MBNL2 promoter was associated with hypomethylation of the specific cytosine-phosphate-guanine (CpG) sites. Reduced MBNL2 expression in cisplatin-sensitive cell lines was restored by treatment with a DNA demethylation agent, suggesting epigenetic regulation of MBNL2 expression by promoter methylation. Furthermore, depletion of MBNL2 in cisplatin-resistant cells induced cytotoxicity in response to cisplatin, whereas overexpression of MBNL2 in cisplatin-sensitive cells increased chemoresistance, indicating that MBNL2 plays a vital role in developing chemoresistance in ovarian cancer cells. Furthermore, we performed meta-analysis using fourteen publicly available datasets to assess the association between expression of MBNL2 and overall survival in patients with serous-type ovarian cancer. The pooled Hazard ratios (HRs) estimate was significantly greater than 1 for overall survival (HR=1.09, p-value=0.0034). The association was more significant (HR=1.12, p-value=0.001) when tumor stage was added to the survival analysis as a covariate. The meta-analysis revealed that high expression of MBNL2 was significantly associated with poor prognosis and a higher risk of death in ovarian cancer patients with serous tumor. Additionally, we further validated the MBNL2 mRNA expression in primary ovarian tumor tissues. The statistically significant upregulation of MBNL2 mRNA expression was observed in cisplatin-resistant patients compared to that of cisplatin-sensitive patients. Our findings suggest MBNL2 may be a potential therapeutic target for the prevention of chemoresistance to cisplatin in ovarian cancer. Citation Format: Woong Ju, Hye Youn Sung, Jung-Hyuck Ahn. Overexpression of Muscleblind Like Splicing Regulator 2 (MBNL2) enhances cisplatin resistance in ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B091.