N4-Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF-1α Positive Feedback Loop.
Adv Sci (Weinh)
; 10(23): e2300898, 2023 08.
Article
em En
| MEDLINE
| ID: mdl-37328448
ABSTRACT
Anti-angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti-angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4-acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF-1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP-sequencing, Ribosome profiling sequencing, RNA-sequencing, and functional studies confirm that NAT10 in turn activates the HIF-1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF-1α positive feedback loop leads to excessive activation of the HIF-1 pathway and induces glycolysis addiction. Combined anti-angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti-angiogenic therapy by combining apatinib with ac4C inhibition.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Ano de publicação:
2023
Tipo de documento:
Article
País de publicação:
ALEMANHA
/
ALEMANIA
/
DE
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DEUSTCHLAND
/
GERMANY