生物
胶质母细胞瘤
癌症研究
N6-甲基腺苷
细胞生物学
遗传学
甲基转移酶
基因
甲基化
作者
Deguan Lv,Cuiqing Zhong,Deobrat Dixit,Kailin Yang,Qiulian Wu,Bhaskar Godugu,Briana C. Prager,Guofeng Zhao,Xiuxing Wang,Qi Xie,Shideng Bao,Chuan He,Dieter Henrik Heiland,Michael G. Rosenfeld,Jeremy Rich
出处
期刊:Molecular Cell
[Elsevier]
日期:2023-12-01
卷期号:83 (23): 4334-4351.e7
被引量:6
标识
DOI:10.1016/j.molcel.2023.10.025
摘要
Summary
Growth factor receptors rank among the most important oncogenic pathways, but pharmacologic inhibitors often demonstrate limited benefit as monotherapy. Here, we show that epidermal growth factor receptor (EGFR) signaling repressed N6-methyladenosine (m6A) levels in glioblastoma stem cells (GSCs), whereas genetic or pharmacologic EGFR targeting elevated m6A levels. Activated EGFR induced non-receptor tyrosine kinase SRC to phosphorylate the m6A demethylase, AlkB homolog 5 (ALKBH5), thereby inhibiting chromosomal maintenance 1 (CRM1)-mediated nuclear export of ALKBH5 to permit sustained mRNA m6A demethylation in the nucleus. ALKBH5 critically regulated ferroptosis through m6A modulation and YTH N6-methyladenosine RNA binding protein (YTHDF2)-mediated decay of the glutamate-cysteine ligase modifier subunit (GCLM). Pharmacologic targeting of ALKBH5 augmented the anti-tumor efficacy of EGFR and GCLM inhibitors, supporting an EGFR-ALKBH5-GCLM oncogenic axis. Collectively, EGFR reprograms the epitranscriptomic landscape through nuclear retention of the ALKBH5 demethylase to protect against ferroptosis, offering therapeutic paradigms for the treatment of lethal cancers.
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