N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis via disrupting NRF1 binding capacity [ALKBH1-RNA-seq]

ABSTRACT: DNA N6-methyladenine (6mA) is an emerging epigenetic modification that regulates various biological processes. Here, we demonstrated the role of DNA 6mA modification in gastric cancer (GC). GC cells and tumors displayed a marked reduction in 6mA levels compared with normal gastric tissues and GES1 cells. 6mA-IP-seq revealed that 6mA was abundant in the surrounding transcription start sites and occurred at consensus motifs. Among the 6mA regulators, ALKBH1, a demethylase, was significantly overexpressed in GC tissues compared to adjacent normal tissues (n=32, P<0.05). Moreover, high ALKBH1 expression was associated with poor survival of patients with GC in three independent GC cohorts (cohort I: n=276, P=0.0093; cohort II: n=136, P=0.001; TCGA dataset: n=381, P=0.0061). Functionally, ALKBH1 knockout increased DNA 6mA and suppressed GC cell growth and cell migration in vitro, and inhibited tumorigenicity and metastasis in vivo. ALKBH1 knockout in mice impairs chemically induced gastric carcinogenesis. Mechanistically, ALKBH1 mediates DNA 6mA demethylation to repress gene expression. In particular, the 6mA sites were enriched in NRF1 binding sequences and targeted for demethylation by ALKBH1. ALKBH1-induced 6mA demethylation inhibited NRF1-driven transcription of downstream targets, including multiple genes involved in the AMPK signaling pathway. Accordingly, ALKBH1 suppressed AMPK signaling, causing a metabolic shift towards the Warburg effect that facilitates tumorigenesis. In conclusion, we revealed, for the first time, that ALKBH1 plays an oncogenic role in GC. ALKBH1 demethylates 6mA within the NRF1-binding regions of tumor suppressor genes to attenuate the binding of NRF1, which subsequently inactivates AMPK signaling and promotes the “Warburg” phenotype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214126 | GEO | 2025/09/22

REPOSITORIES: GEO