Zhongyuan Bao1, Lingyang Hua2, Yangfan Ye1, Daijun Wang2, Chong Li1, Qing Xie2, Hiroaki Wakimoto3, Ye Gong2,4, Jing Ji1,5. 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
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.
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.
Authors: Irene Homminga; Rob Pieters; Anton W Langerak; Johan J de Rooi; Andrew Stubbs; Monique Verstegen; Maartje Vuerhard; Jessica Buijs-Gladdines; Clarissa Kooi; Petra Klous; Pieter van Vlierberghe; Adolfo A Ferrando; Jean Michel Cayuela; Brenda Verhaaf; H Berna Beverloo; Martin Horstmann; Valerie de Haas; Anna-Sophia Wiekmeijer; Karin Pike-Overzet; Frank J T Staal; Wouter de Laat; Jean Soulier; Francois Sigaux; Jules P P Meijerink Journal: Cancer Cell Date: 2011-04-12 Impact factor: 31.743
Authors: Vasanthi S Viswanathan; Matthew J Ryan; Harshil D Dhruv; Shubhroz Gill; Ossia M Eichhoff; Brinton Seashore-Ludlow; Samuel D Kaffenberger; John K Eaton; Kenichi Shimada; Andrew J Aguirre; Srinivas R Viswanathan; Shrikanta Chattopadhyay; Pablo Tamayo; Wan Seok Yang; Matthew G Rees; Sixun Chen; Zarko V Boskovic; Sarah Javaid; Cherrie Huang; Xiaoyun Wu; Yuen-Yi Tseng; Elisabeth M Roider; Dong Gao; James M Cleary; Brian M Wolpin; Jill P Mesirov; Daniel A Haber; Jeffrey A Engelman; Jesse S Boehm; Joanne D Kotz; Cindy S Hon; Yu Chen; William C Hahn; Mitchell P Levesque; John G Doench; Michael E Berens; Alykhan F Shamji; Paul A Clemons; Brent R Stockwell; Stuart L Schreiber Journal: Nature Date: 2017-07-05 Impact factor: 49.962