MBNL2 enhances cisplatin resistance by regulating apoptosis in ovarian cancer cells
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Although cisplatin is an effective anticancer agent for treatingovarian cancer, it encounters significant resistance. A full understandingof the mechanisms behind cisplatin resistance has notbeen achieved. This study identifies MBNL2 as a crucial regulatorof cellular responses to cisplatin, examining variations ingene expression and methylation profiles between cisplatinsensitiveand -resistant ovarian cancer cells. Cells resistant tocisplatin exhibited increased MBNL2 mRNA expression andsignificant demethylation at promoter CpG sites. Treating ovariancancer cell lines with a DNA demethylating agent significantlyraised MBNL2 mRNA expression, indicating that epigeneticmechanisms involving DNA methylation control MBNL2 expression. Modulating MBNL2 levels altered the response tocisplatin through survival pathways that shield cells fromcisplatin-induced apoptosis. Overexpressing MBNL2 enhancedresistance, while its depletion heightened cisplatin sensitivity. Furthermore, MBNL2 mRNA levels differed among patientsbased on their response to platinum-based chemotherapeutics. Patients resistant to these drugs had higher MBNL2 mRNAlevels, effectively distinguishing them from those who weresensitive (AUC = 0.89, P = 0.0308). A meta-analysis of seventeendatasets confirmed that lower MBNL2 expression levelsare associated with a better chemotherapy response and longerrelapse-free survival. Conversely, higher MBNL2 expressionlevels correlated with increased recurrence rates and reducedsurvival. Thus, MBNL2 may serve as a promising prognosticand therapeutic target for overcoming cisplatin resistance.
Abstract
Although cisplatin is an effective anticancer agent for treatingovarian cancer, it encounters significant resistance. A full understandingof the mechanisms behind cisplatin resistance has notbeen achieved. This study identifies MBNL2 as a crucial regulatorof cellular responses to cisplatin, examining variations ingene expression and methylation profiles between cisplatinsensitiveand -resistant ovarian cancer cells. Cells resistant tocisplatin exhibited increased MBNL2 mRNA expression andsignificant demethylation at promoter CpG sites. Treating ovariancancer cell lines with a DNA demethylating agent significantlyraised MBNL2 mRNA expression, indicating that epigeneticmechanisms involving DNA methylation control MBNL2 expression. Modulating MBNL2 levels altered the response tocisplatin through survival pathways that shield cells fromcisplatin-induced apoptosis. Overexpressing MBNL2 enhancedresistance, while its depletion heightened cisplatin sensitivity. Furthermore, MBNL2 mRNA levels differed among patientsbased on their response to platinum-based chemotherapeutics. Patients resistant to these drugs had higher MBNL2 mRNAlevels, effectively distinguishing them from those who weresensitive (AUC = 0.89, P = 0.0308). A meta-analysis of seventeendatasets confirmed that lower MBNL2 expression levelsare associated with a better chemotherapy response and longerrelapse-free survival. Conversely, higher MBNL2 expressionlevels correlated with increased recurrence rates and reducedsurvival. Thus, MBNL2 may serve as a promising prognosticand therapeutic target for overcoming cisplatin resistance.