KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation [CUT&Tag]
KMT2C is a frequently mutated gene in meningiomas, however, its functional role in meningioma pathogenesis remains poorly understood. Here we demonstrate that KMT2C expression is reduced in high-grade meningiomas and that its deficiency promotes tumor progression by inactivating the Hippo pathway. Mechanistically, KMT2C loss diminishes H3K27ac levels at transcription start sites (TSS) and disrupts chromatin accessibility, leading to transcriptional downregulation of NF2 and subsequent dysregulation of Hippo signaling. We further reveal that KMT2C deficiency impairs the acetyltransferase activity of CBP/EP300, thereby reducing H3K27ac deposition, while the chromatin binding of CBP/EP300 remains unaffected following KMT2C knockout. Treatment with the histone deacetylase inhibitor TSA restores H3K27ac levels and reactivates NF2 expression in KMT2C-deficient meningiomas. Notably, KMT2C loss sensitizes meningioma cells to ferroptosis, and the ferroptosis inducer erastin significantly suppresses tumor growth both in vitro and in vivo. These findings establish a foundation for developing targeted therapies for meningioma patients with KMT2C deficiency. Overall design: By knockout the expression of KMT2C in meningioma cells, the role and mechanism of KMT2C in meningioma were explored.