2. Academic Validation
  3. EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma

EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma

  • Mol Cell. 2023 Dec 7;83(23):4334-4351.e7. doi: 10.1016/j.molcel.2023.10.025.
Deguan Lv 1,  Cuiqing Zhong 1,  Deobrat Dixit 2,  Kailin Yang 3,  Qiulian Wu 1,  Bhaskar Godugu 4,  Briana C Prager 5,  Guofeng Zhao 6,  Xiuxing Wang 7,  Qi Xie 8,  Shideng Bao 9,  Chuan He 10,  Dieter Henrik Heiland 11,  Michael G Rosenfeld 6,  Jeremy N Rich 12
Affiliations

Affiliations

  • 1 UPMC Hillman Cancer Center and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 2 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 3 Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
  • 5 Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 6 Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 7 School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
  • 8 Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 9 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 10 Department of Chemistry and Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
  • 11 Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.
  • 12 UPMC Hillman Cancer Center and Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: [email protected].
PMID: 37979586 DOI: 10.1016/j.molcel.2023.10.025
Abstract

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.

Keywords

ALKBH5; EGFR; GCLM; SRC; YTHDF2; cancer stem cell; ferroptosis; glioblastoma; glioblastoma stem cell; m(6)A.

Figures
Products