Silencing KMT2A with siRNA induces apoptosis and cell cycle arrest in high-grade serous ovarian carcinoma cells by modulating GOF p53-dependent pathways, highlighting its potential as a therapeutic target.

High-grade serous ovarian carcinoma (HGSOC) is the deadliest gynecological cancer, often characterized by TP53 mutations that result in gain-of-function (GOF) p53, contributing to the aggressive nature of the disease. Recent studies demonstrated that GOF p53 drives cancer progression by recruiting epigenetic regulators that activate the expression of oncogenic genes. One such regulator is lysine methyltransferase 2 A (KMT2A), an enzyme that modulates gene expression by methylating histone H3 at lysine 4. In this study, we explored the expression and functional role of KMT2A in HGSOC progression. The GSE66957 and GSE26712 datasets, along with GeneMANIA and STRING databases, were used to examine KMT2A expression and predict interaction networks in HGSOC. Then, expression levels were validated in ovarian cancer tissues and cell lines via qRT-PCR, western blotting, and immunohistochemistry. KMT2A silencing was achieved using KMT2A-specific siRNA in OVCAR3 cells, with functional impacts on apoptosis and cell cycle progression examined through flow cytometry. The results showed a significant upregulation of KMT2A mRNA and protein levels in HGSOC tissues and cell line. KMT2A knockdown induced cell cycle arrest and apoptosis by modulating cell cycle and apoptotic genes. Moreover, KMT2A silencing significantly reduced GOF p53, YAP, phosphorylated AKT, and their downstream targets, suggesting that KMT2A may cooperate with GOF p53 to promote HGSOC progression via YAP, AKT, and p21 signaling pathways. In conclusion, our data indicate that KMT2A contributes to HGSOC-associated cellular phenotypes in the OVCAR3 model; however, further studies are needed to clarify its broader role in HGSOC and its potential as a therapeutic target.