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

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

SUBMITTER: Lv D 

PROVIDER: S-EPMC10842222 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature