DNA的N6-甲基腺嘌呤（6mA）是一种表观遗传修饰，可以调节各种生物过程。我们的研究表明，胃癌细胞和肿瘤与正常的胃组织和细胞相比，6mA水平显著降低。6mA在周围的转录起始位点中丰富，出现在共识序列中。在6mA的调节因子中，一种去甲基化酶ALKBH1在胃癌组织中的表达显著高于相邻正常组织。此外，高表达与GC患者的不良生存率有关。在小鼠中，ALKBH1基因敲除会影响化学诱导的胃癌发生。机制上，ALKBH1介导DNA 6mA去甲基化从而抑制基因表达。具体地，6mA位点富含NRF1结合序列，成为ALKBH1去甲基化的靶点。ALKBH1介导的6mA去甲基化抑制了NRF1驱动的下游靶标的转录，包括多个参与AMP激活蛋白激酶（AMPK）信号通路的基因。因此，ALKBH1抑制了AMPK信号通路，导致代谢的转化进入沃尔布效应，从而促进肿瘤发生。版权所有©2023年作者。由Elsevier Inc.出版，版权所有。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.