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.

KMT2C是脑膜瘤中的高频突变基因，然而其在脑膜瘤发病机制中的功能作用仍未被充分阐明。本研究证实，高级别脑膜瘤中KMT2C的表达水平显著下调，且该基因缺失会通过失活Hippo通路（Hippo pathway）促进肿瘤进展。
机制上，KMT2C缺失会降低转录起始位点（Transcription Start Sites, TSS）处的H3K27ac修饰水平，并破坏染色质可及性，导致NF2基因转录下调，进而引发Hippo信号通路失调。本研究进一步揭示，KMT2C缺失会损害CREB结合蛋白/EP300（CBP/EP300）的乙酰转移酶活性，从而减少H3K27ac的沉积；而KMT2C敲除后，CBP/EP300的染色质结合能力并未受到影响。
使用组蛋白去乙酰化酶抑制剂曲古抑菌素A（Trichostatin A, TSA）处理KMT2C缺失型脑膜瘤细胞，可恢复其H3K27ac修饰水平，并重新激活NF2的表达。值得注意的是，KMT2C缺失会使脑膜瘤细胞对铁死亡（ferroptosis）敏感，而铁死亡诱导剂艾拉司汀（erastin）可在体外与体内显著抑制肿瘤生长。
上述研究结果为开发针对KMT2C缺失型脑膜瘤患者的靶向治疗方案奠定了理论基础。
整体实验设计：通过在脑膜瘤细胞中敲除KMT2C的表达，探究该基因在脑膜瘤发生发展中的作用与分子机制。