The N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis by disrupting NRF1 binding capacity.

DNA N6-methyladenine (6mA) is an epigenetic modification that regulates various biological processes. Here, we show that gastric cancer (GC) cells and tumors display a marked reduction in 6mA levels compared with normal gastric tissues and cells. 6mA is abundant in the surrounding transcription start sites and occurs at consensus motifs. Among the 6mA regulators, ALKBH1, a demethylase, is significantly overexpressed in GC tissues compared with adjacent normal tissues. Moreover, high ALKBH1 expression is associated with poor survival of patients with GC. ALKBH1 knockout in mice impairs chemically induced gastric carcinogenesis. Mechanistically, ALKBH1 mediates DNA 6mA demethylation to repress gene expression. In particular, the 6mA sites are enriched in NRF1 binding sequences and targeted for demethylation by ALKBH1. ALKBH1-induced 6mA demethylation inhibits NRF1-driven transcription of downstream targets, including multiple genes involved in the AMP-activated protein kinase (AMPK) signaling pathway. Accordingly, ALKBH1 suppresses AMPK signaling, causing a metabolic shift toward the Warburg effect, which facilitates tumorigenesis.