FTO demethylates m6A modifications in CDKAL1 mRNA and promotes gastric cancer chemoresistance by altering mitochondrial dynamics

Clin Exp Pharmacol Physiol. 2023 Apr;50(4):307-315. doi: 10.1111/1440-1681.13748. Epub 2023 Feb 7.

Abstract

N6-methyladenosine (m6A) modification is the most common mRNA modification that is considered a new layer of mRNA epigenetic regulation. Demethylase fat mass and obesity-associated protein (FTO) are important in the dynamic regulation of m6A, but their role in gastric cancer (GC) is not fully understood. This study revealed that FTO and CDKAL1 were up-regulated in GC cells and tissue. CDKAL1 is the downstream target of FTO-mediated m6A modification, with FTO promoting GC cell proliferation through CDKAL1 and inducing mitochondrial fusion, eventually causing GC chemoresistance. In conclusion, FTO contributes to the increasing resistance of GC cells to 5-fluorouracil (5-Fu) by upregulating CDKAL1 and inducing mitochondrial fusion.

Keywords: CDKAL1; FTO; chemoresistance; gastric cancer; mitochondrial.

MeSH terms

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / genetics
  • Drug Resistance, Neoplasm
  • Epigenesis, Genetic
  • Humans
  • Mitochondrial Dynamics
  • RNA, Messenger / genetics
  • Stomach Neoplasms* / genetics
  • tRNA Methyltransferases / genetics
  • tRNA Methyltransferases / metabolism

Substances

  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • CDKAL1 protein, human
  • FTO protein, human
  • RNA, Messenger
  • tRNA Methyltransferases