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

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 wildtype). The impact of NF2 and E-cadherin on ferroptosis were examined by 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.

Hsp90 Induces Acsl4-dependent Glioma Ferroptosis via Dephosphorylate Ser637 at Drp1

“…Notably, the dose of erastin (10 mg/kg, i.p., twice every other day) we explored and used in treating glioma was lower than that we used in meningioma treatment before, which was 15 mg/kg, i.p., twice every other day [49]. Moreover, compared with the data published before, we found that Sun X used 20 mg/kg intravenously (i.v.…”

The Role of Iron in Cancer Progression

“…This suggests that oxidation of SOX2 could be a potential target for ferroptosis-targeted treatment for cancer (130). Moreover, as cell density-dependent E-cadherin and Merlin/Neurofibromin (NF2) loss can induce ferroptosis, Bao et al found that NF2-inactivated meningioma cells were sensitive to Erastin-induced ferroptosis by analyzing 35 meningioma samples (10 NF2 loss and 25 NF2 wildtype), and further confirmed that myoenhancer factor 2C (MEF2C) acted as a promoter of NF2 and CDH1, thereby inhibiting ferroptosisrelated lipid peroxidation and meningioma cell death (131). Notably, Kremer et al indicated that aspartate aminotransferase (GOT1) could damage mitochondrial oxidative phosphorylation and promote catabolism, resulting in the increase of unstable iron pool and susceptibility to ferroptosis, this effect suggests that inhibiting GOT1 could destroy the redox balance and proliferation in pancreatic ductal carcinoma, and establishes a biochemical link between GOT1 and ferroptosis (132).…”

“…Moreover, as cell density-dependent E-cadherin and Merlin/Neurofibromin (NF2) loss can induce ferroptosis, Bao et al. found that NF2-inactivated meningioma cells were sensitive to Erastin-induced ferroptosis by analyzing 35 meningioma samples (10 NF2 loss and 25 NF2 wildtype), and further confirmed that myoenhancer factor 2C ( MEF2C) acted as a promoter of NF2 and CDH1 , thereby inhibiting ferroptosis-related lipid peroxidation and meningioma cell death ( 131 ). Notably, Kremer et al.…”

Iron Transporters and Ferroptosis in Malignant Brain Tumors

“…Silencing MEF2C, the expression levels of NF2 and E-cadherin in meningiomas decreased, which inhibited the growth of meningiomas mediated by ferroptosis ( Figure 1 ). Therefore, MEF2C can be used as a potential molecular target for the treatment of aggressive meningiomas through modulating ferroptosis ( 107 ).…”