MEF2C silencing downregulates NF2 and E-cadherin and enhances Erastin-induced ferroptosis in meningioma

Author:

Bao Zhongyuan1,Hua Lingyang2,Ye Yangfan1,Wang Daijun2,Li Chong1,Xie Qing2,Wakimoto Hiroaki3,Gong Ye24,Ji Jing15

Affiliation:

1. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

2. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

3. Brain Tumor Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

4. Department of Critical Care Medicine, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

5. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China

Abstract

Abstract Background Ferroptosis, a programmed cell death characterized by lipid peroxidation, is implicated in various diseases including cancer. Although cell density-dependent E-cadherin and Merlin/Neurofibromin (NF2) loss can modulate ferroptosis, the role of ferroptosis and its potential link to NF2 status and E-cadherin expression in meningioma remain unknown. Methods Relationship between ferroptosis modulators expression and NF2 mutational status was examined in 35 meningiomas (10 NF2 loss and 25 NF2 wild type). The impact of NF2 and E-cadherin on ferroptosis were examined by lactate dehydrogenase (LDH) release, lipid peroxidation, and western blot assays in IOMM-Lee, CH157, and patient-derived meningioma cell models. Luciferase reporter and chromatin immunoprecipitation assays were used to assess the ability of MEF2C (myocyte enhancer factor 2C) to drive expression of NF2 and CDH1 (E-cadherin). Therapeutic efficacy of Erastin-induced ferroptosis was tested in xenograft mouse models. Results Meningioma cells with NF2 inactivation were susceptible to Erastin-induced ferroptosis. Meningioma cells grown at higher density increased expression of E-cadherin, which suppressed Erastin-induced ferroptosis. Maintaining NF2 and E-cadherin inhibited ferroptosis-related lipid peroxidation and meningioma cell death. MEF2C was found to drive the expression of both NF2 and E-cadherin. MEF2C silencing enhanced Erastin-induced ferroptotic meningioma cell death and lipid peroxidation levels in vitro, which was limited by forced expression of MEF2C targets, NF2 and E-cadherin. In vivo, anti-meningioma effect of Erastin was augmented by MEF2C knockdown and was counteracted by NF2 or E-cadherin. Conclusions NF2 loss and low E-cadherin create susceptibility to ferroptosis in meningioma. MEF2C could be a new molecular target in ferroptosis-inducing therapies for meningioma.

Funder

National Natural Science Foundation of China

Jiangsu Province’s Key Discipline of Medicine

Jiangsu Province Innovative Team

Shanghai Sailing Program

Meningioma Mommas

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Clinical Neurology,Oncology

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