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KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297610 | GEO | 2025/12/13

REPOSITORIES: GEO

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KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation [CUT&Tag]

Project description: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.

2025-12-12 | GSE312824 | GEO

Integrated proteomic, DNA methylation, and targeted Next Generation Sequencing reveals relevant heterogeneity in lower-grade meningioma and a new target in NF2 mutated meningiomas

Project description:Meningiomas, the most common primary brain tumours, are classified by the World Health Organization (WHO) into grades 1, 2, and 3. Some grade 1 tumours exhibit increased clinical aggressiveness with the biallelic mutation of Neurofibromatosis 2 (NF2) being the most frequent mutation reported. In our study, we analysed the most common driver mutations (NF2, AKT1, KLF4, and TRAF7) in meningioma by proteomics and genomics focussing on lower grade tumours. Our genomic data revealed co-occurrences of non-NF2 mutations in lower-grade meningiomas suggesting synergistic effects supporting tumour growth. NF2-/- meningiomas showed distinct proteomic clustering, with different mutations found in these clusters. Additionally, proteomics identified ANXA3 in NF2-/- meningioma and its role in proliferation was confirmed in grade1 and subsequently grade 3 tumours in vitro and with abolished growth when tested in meningioma mouse model. These findings highlight new targets in different meningioma backgrounds presenting ANXA3 as a potential therapeutic target for meningioma treatment.

2025-07-02 | PXD058653 | Pride

Integrated proteomic, DNA methylation, and targeted Next Generation Sequencing reveals relevant heterogeneity in lower-grade meningioma and a new target in NF2 mutated meningiomas

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GSTM1 null genotype underpins recurrence of NF2 meningiomas

Project description:Introduction: Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited. Objective: To identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas. Methods: Transcriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort. Results: Recurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed. Conclusions: The GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.

2024-12-09 | GSE283616 | GEO

KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation

Project description:KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation

| PRJNA1265258 | ENA

Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

Project description:We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics. Analysis of meningioma gene expression data for each mutation subtype. Includes gene expression data from 75 unique meningiomas and 39 replicates.

2014-05-29 | E-GEOD-58037 | biostudies-arrayexpress

"Immunogenic subtype" characterised by macrophages infiltration predominantly comprise meningiomas in neurofibromatosis type 2 patients

Project description:Aims: Whereas recent molecular analysis has revealed that sporadic meningioma has various genetic, epigenetic, and transcriptomic profiles, those of meningioma in NF2 patients are not fully elucidated. This study probed meningiomas' clinical, histological, and molecular characteristics in NF2 patients. Methods: A long-term retrospective follow-up (13.5 ± 5.5 years) study involving 159 meningiomas in NF2 patients was performed. We assessed their characteristics by performing immunohistochemistry (IHC), bulk-RNA sequencing, and copy number analysis. All variables of meningiomas in NF2 patients were compared with those of 189 sporadic NF2-altered meningiomas. Results: Most meningiomas in NF2 patients were stable, and the mean annual growth rate was 1.0 ± 1.8 cm3/yr. Twenty-eight meningiomas (17.6%) in 25 patients (43.1%) were resected during the follow-up period. WHO grade 1 meningiomas in NF2 patients` were more frequent than in sporadic NF2-altered meningiomas (92.9% vs 80.9%). Transcriptomic analysis for NF2 patients`/sporadic NF2-altered WHO grade 1 meningiomas (n = 14 versus 15, respectively) showed that tumours in NF2 patients had still higher immune response and immune cell infiltration than sporadic NF2-altered meningiomas. Furthermore, RNA-seq/IHC-derived immunophenotyping corroborated this higher immune response by identifying myeloid cell infiltration, especially macrophages. Conclusions: Clinical, histological, and transcriptomic analyses for meningiomas in NF2 patients demonstrated that meningiomas in NF2 patients showed less aggressive behaviour than sporadic NF2-altered meningiomas and elicited marked immune response by identifying myeloid cell infiltration, especially macrophages.

2023-08-08 | GSE232528 | GEO

Merlin S13 phosphorylation controls meningioma Wnt signaling and magnetic resonance imaging features

Project description:Meningiomas are the most common primary intracranial tumors and are associated with inactivation of the tumor suppressor NF2/Merlin, but one-third of meningiomas retain Merlin expression and typically have favorable clinical outcomes. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that predict meningioma outcomes and could be used to guide treatment de-escalation or imaging surveillance of Merlin-intact meningiomas are lacking. Here we integrate single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma cells, xenografts, and human patients to define biochemical mechanisms and an imaging biomarker that distinguish Merlin-intact meningiomas with favorable clinical outcomes from meningiomas with unfavorable clinical outcomes. We find Merlin drives meningioma Wnt signaling and tumor growth through a feed-forward mechanism that requires Merlin dephosphorylation on serine 13 (S13) to attenuate inhibitory interactions with β-catenin and activate the Wnt pathway. Meningioma MRI analyses of xenografts and human patients show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC) on diffusionweighted imaging. In sum, our results shed light on Merlin posttranslational modifications that regulate meningioma Wnt signaling and tumor growth in tumors without NF2/Merlin inactivation. To translate these findings to clinical practice, we establish a non-invasive imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with favorable meningiomas.

2024-07-04 | PXD053578 | Pride

KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation [CUT&Tag]

Project description:KMT2C deficiency promotes meningioma progression through H3K27ac-mediated HIPPO Pathway Inactivation [CUT&Tag]

| PRJNA1377469 | ENA

High-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling.

Project description:Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset is of higher grade, recurs even after multiple surgeries, and frequently fatal. Around half of meningiomas harbor inactivating mutations in NF2. While low-grade NF2 mutant meningiomas harbor few additional mutations in addition to NF2 inactivation, high-grade NF2 mutant tumors frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as an oncogene in NF2 mutant meningiomas. Here, we show that high-grade NF2 mutant meningiomas downregulate YAP1 signaling, in part through upregulating the expression of the YAP1 competitor VGLL4 and the YAP1 upstream regulators FAT3/4. Overexpression of VGLL4 resulted in the downregulation of YAP activity and the growth inhibition of low-grade NF2 mutant meningioma cells. Our results have important implications for the efficacy of therapies targeting oncogenic YAP1 in high-grade NF2 mutant meningiomas.

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