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

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 N Rich

doi:10.1016/j.molcel.2023.10.025

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

Journal article

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

Deguan Lv, Cuiqing Zhong, Deobrat Dixit, Kailin Yang, Qiulian Wu, Bhaskar Godugu, Briana C Prager, Guofeng Zhao, Xiuxing Wang, Qi Xie, …

Molecular cell, Vol.83(23), pp.4334-4351.e7

12/07/2023

DOI: 10.1016/j.molcel.2023.10.025

PMCID: PMC10842222

PMID: 37979586

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https://pmc.ncbi.nlm.nih.gov/articles/PMC10842222/pdf/nihms-1941941.pdfView

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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 N -methyladenosine (m A) levels in glioblastoma stem cells (GSCs), whereas genetic or pharmacologic EGFR targeting elevated m A levels. Activated EGFR induced non-receptor tyrosine kinase SRC to phosphorylate the m A demethylase, AlkB homolog 5 (ALKBH5), thereby inhibiting chromosomal maintenance 1 (CRM1)-mediated nuclear export of ALKBH5 to permit sustained mRNA m A demethylation in the nucleus. ALKBH5 critically regulated ferroptosis through m A 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.

Adenosine - metabolism

AlkB Homolog 5, RNA Demethylase - genetics

AlkB Homolog 5, RNA Demethylase - metabolism

ErbB Receptors - genetics

Ferroptosis - genetics

Glioblastoma - drug therapy

Glioblastoma - genetics

Humans

RNA, Messenger - genetics

Details

Title: Subtitle: EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma
Creators: Deguan Lv - UPMC Hillman Cancer Center
Cuiqing Zhong - UPMC Hillman Cancer Center
Deobrat Dixit - Sanford Burnham Prebys Medical Discovery Institute
Kailin Yang - Cleveland Clinic
Qiulian Wu - UPMC Hillman Cancer Center
Bhaskar Godugu - University of Pittsburgh
Briana C Prager - Massachusetts General Hospital
Guofeng Zhao - University of California San Diego
Xiuxing Wang - Nanjing Medical University
Qi Xie - Westlake University
Shideng Bao - Cleveland Clinic Lerner College of Medicine
Chuan He - University of Chicago
Dieter Henrik Heiland - University Medical Center Freiburg
Michael G Rosenfeld - University of California San Diego
Jeremy N Rich - UPMC Hillman Cancer Center
Resource Type: Journal article
Publication Details: Molecular cell, Vol.83(23), pp.4334-4351.e7
DOI: 10.1016/j.molcel.2023.10.025
PMID: 37979586
PMCID: PMC10842222
NLM abbreviation: Mol Cell
ISSN: 1097-2765
eISSN: 1097-4164
Grant note: R01 CA268634 / NCI NIH HHS R35 CA197718 / NCI NIH HHS R01 CA238662 / NCI NIH HHS R01 NS103434 / NINDS NIH HHS T32 CA094186 / NCI NIH HHS R01 NS115831 / NINDS NIH HHS
Language: English
Date published: 12/07/2023
Academic Unit: Radiation Oncology
Record Identifier: 9984696718602771

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