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journal article·2026-04Open access

KMT2C Loss Promotes NF2‐Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling

Liuchao Zhang, Yangfan Ye, Wei Gu, Xinyue Wang, Nuo Chen, Qixin He, Lei Xu, Pengzhan Zhao, Guoqiang Fu, Guangyao Yuan, Wenqian Shi, Honglu Chao, Yiming Tu, Jing Ji

Advanced Science· Volume 13· Issue 20
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Source abstract

Abstract

ABSTRACT High‐grade meningiomas remain clinically challenging due to their aggressive behavior and limited therapeutic options. Although mutations and dysregulation of KMT2 family members have been implicated in various cancers, their functional significance in meningioma remains unclear. While NF2 alterations are the most common drivers of meningioma pathogenesis, the mechanisms regulating NF2 transcription in NF2‐intact tumors are poorly understood. Here, we demonstrate that KMT2C expression is markedly reduced in high‐grade meningiomas and that loss of KMT2C promotes proliferation and invasion in NF2–wild‐type meningioma cells. Mechanistically, KMT2C deficiency suppresses NF2 transcription and inactivates Hippo signaling, leading to enhanced oncogenic activity and increased sensitivity to ferroptosis. Loss of KMT2C impairs the acetyltransferase activity of CBP/EP300, resulting in a global reduction of H3K27ac and transcriptional silencing of NF2. Pharmacological restoration of histone acetylation with the HDAC inhibitor Trichostatin A (TSA) effectively suppressed tumor growth. Collectively, our findings identify KMT2C as a key epigenetic regulator linking promoter histone acetylation, NF2–Hippo pathway activity, and ferroptosis susceptibility. These results provide mechanistic insights into high‐grade meningioma progression and highlight ferroptosis induction and epigenetic modulation as promising therapeutic strategies for NF2–wild‐type, KMT2C‐deficient meningiomas.
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Research context

OpenAlex topics: Meningioma and schwannoma management · Neurofibromatosis and Schwannoma Cases · Chromatin Remodeling and Cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurosurgery The First Affiliated Hospital with Nanjing Medical University Nanjing Jiangsu P. R. China

Neurovascular Center Changhai Hospital, Naval Medical University Shanghai P. R. China

Department of Neurosurgery Division of Life Sciences and Medicine The First Affiliated Hospital of USTC University of Science and Technology of China Hefei Anhui P. R. China

Department of Neurosurgery Northern Jiangsu People's Hospital Nanjing P. R. China

Department of Neurosurgery Research Center of Clinical Medicine Affiliated Hospital of Nantong University, Medical School of Nantong University Nantong Jiangsu P. R. China

Institute For Brain Tumors Jiangsu Key Lab of Cancer Biomarkers Prevention and Treatment Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University Nanjing Jiangsu P. R. China

Department of Neurosurgery The Affiliated Kizilsu Kirghiz Autonomous Prefecture People's Hospital of Nanjing Medical University Artux Xinjiang P. R. China

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Priority Academic Program Development of Jiangsu Higher Education Institutions · China Postdoctoral Science Foundation

References (48)

Show source-provided references
1. 10.1093/neuonc/noae25310.1093/neuonc/noae253 ↗
2. 10.1093/neuonc/noac20210.1093/neuonc/noac202 ↗
3. 10.1056/NEJMoa240098510.1056/NEJMoa2400985 ↗
4. 10.3171/foc/2008/24/5/e710.3171/foc/2008/24/5/e7 ↗
5. 10.1055/s‐0036‐157976610.1055/s‐0036‐1579766 ↗
6. 10.1038/s41392‐022‐01191‐910.1038/s41392‐022‐01191‐9 ↗
7. 10.1146/annurev‐biochem‐013118‐11182910.1146/annurev‐biochem‐013118‐111829 ↗
8. 10.1038/s41422‐020‐00441‐110.1038/s41422‐020‐00441‐1 ↗
9. 10.1038/s41580‐020‐00324‐810.1038/s41580‐020‐00324‐8 ↗
10. 10.1093/neuonc/noab11410.1093/neuonc/noab114 ↗
11. 10.1038/nrc392910.1038/nrc3929 ↗
12. 10.1186/s13045‐021‐01050‐010.1186/s13045‐021‐01050‐0 ↗
13. 10.1186/s12943‐022‐01542‐810.1186/s12943‐022‐01542‐8 ↗
14. 10.1038/s43018‐022‐00361‐610.1038/s43018‐022‐00361‐6 ↗
15. 10.1038/s41556‐024‐01446‐310.1038/s41556‐024‐01446‐3 ↗
16. 10.1038/s41591‐018‐0034‐610.1038/s41591‐018‐0034‐6 ↗
17. 10.1016/j.canlet.2019.05.02410.1016/j.canlet.2019.05.024 ↗
18. 10.1038/s41587‐021‐00869‐910.1038/s41587‐021‐00869‐9 ↗
19. 10.1016/j.molcel.2017.04.01810.1016/j.molcel.2017.04.018 ↗
20. 10.1016/j.tplants.2015.07.00510.1016/j.tplants.2015.07.005 ↗
21. 10.1038/s41477‐024‐01623‐010.1038/s41477‐024‐01623‐0 ↗
22. 10.1093/nar/gkx23410.1093/nar/gkx234 ↗
23. 10.1093/neuonc/noac12710.1093/neuonc/noac127 ↗
24. 10.1227/neu.000000000000227210.1227/neu.0000000000002272 ↗
25. 10.1186/s40478‐022‐01362‐310.1186/s40478‐022‐01362‐3 ↗
26. 10.1038/s41586‐019‐1426‐610.1038/s41586‐019‐1426‐6 ↗
27. 10.1093/cvr/cvab29110.1093/cvr/cvab291 ↗
28. 10.1093/neuonc/noab24410.1093/neuonc/noab244 ↗
29. 10.1093/brain/awac34210.1093/brain/awac342 ↗
30. 10.1038/s41467‐022‐33323‐810.1038/s41467‐022‐33323‐8 ↗
31. 10.1016/j.critrevonc.2024.10434910.1016/j.critrevonc.2024.104349 ↗
32. 10.1038/s41586‐019‐1705‐210.1038/s41586‐019‐1705‐2 ↗
33. 10.1158/2159‐8290.Cd‐23‐122010.1158/2159‐8290.Cd‐23‐1220 ↗
34. 10.1038/s41589‐019‐0264‐z10.1038/s41589‐019‐0264‐z ↗
35. 10.1002/advs.20240884510.1002/advs.202408845 ↗
36. 10.1016/j.biomaterials.2015.02.01510.1016/j.biomaterials.2015.02.015 ↗
37. 10.1186/s13046‐017‐0647‐510.1186/s13046‐017‐0647‐5 ↗
38. 10.7150/thno.7322310.7150/thno.73223 ↗
39. 10.1101/gad.339762.12010.1101/gad.339762.120 ↗
40. 10.3390/ijms1904098810.3390/ijms19040988 ↗
41. 10.1038/s41467‐025‐56634‐y10.1038/s41467‐025‐56634‐y ↗
42. 10.1111/cas.1313810.1111/cas.13138 ↗
43. 10.1093/neuonc/noab03610.1093/neuonc/noab036 ↗
44. 10.1038/ng.355010.1038/ng.3550 ↗
45. 10.1038/s41467‐023‐39735‐410.1038/s41467‐023‐39735‐4 ↗
46. 10.1016/j.cell.2009.06.04910.1016/j.cell.2009.06.049 ↗
47. 10.1016/j.molcel.2024.02.03010.1016/j.molcel.2024.02.030 ↗
48. 10.1186/s13059‐023‐02883‐310.1186/s13059‐023‐02883‐3 ↗