UPMC Hillman Cancer Center and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Mol Cell. 2023 Dec 7;83(23):4334-4351.e7. doi: 10.1016/j.molcel.2023.10.025. Epub 2023 Nov 17.
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 N-methyladenosine (mA) levels in glioblastoma stem cells (GSCs), whereas genetic or pharmacologic EGFR targeting elevated mA levels. Activated EGFR induced non-receptor tyrosine kinase SRC to phosphorylate the mA demethylase, AlkB homolog 5 (ALKBH5), thereby inhibiting chromosomal maintenance 1 (CRM1)-mediated nuclear export of ALKBH5 to permit sustained mRNA mA demethylation in the nucleus. ALKBH5 critically regulated ferroptosis through mA 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.
生长因子受体属于最重要的致癌途径之一，但作为单一疗法，药理抑制剂的疗效往往有限。在这里，我们表明表皮生长因子受体（EGFR）信号抑制胶质母细胞瘤干细胞（GSCs）中的 N-甲基腺苷（mA）水平，而 EGFR 的遗传或药理靶向作用则提高了 mA 水平。激活的 EGFR 诱导非受体酪氨酸激酶 SRC 磷酸化 mA 去甲基酶 AlkB 同源物 5（ALKBH5），从而抑制染色体维持 1（CRM1）介导的 ALKBH5 核输出，以允许核内持续的 mRNA mA 去甲基化。ALKBH5 通过 mA 调节和 YTH N6-甲基腺苷 RNA 结合蛋白（YTHDF2）介导的谷氨酸-半胱氨酸连接酶修饰亚基（GCLM）降解来严格调控铁死亡。ALKBH5 的药理靶向增强了 EGFR 和 GCLM 抑制剂的抗肿瘤疗效，支持 EGFR-ALKBH5-GCLM 致癌轴。总的来说，EGFR 通过核保留 ALKBH5 去甲基酶来重新编程表观转录组景观，以防止铁死亡，为治疗致命癌症提供了治疗范例。
