Published on Jan. 8, 2020 in Biochem Biophys Res Commun volume 521(2).

PubMed ID: 31677788

DOI: S0006-291X(19)32053-4

Abstract:

Obstructive sleep apnea (OSA) is closely associated with cancer progression andcancer-related mortality. N6-methyladenosine (m(6)A) is involved in the process ofintermittent hypoxia (IH) promoting tumor progression. However, it is unclear howm(6)A regulates the development of lung adenocarcinoma under IH. In this study, wefound that ALKBH5 was elevated in lung adenocarcinoma cells and subcutaneous tumorsin mice under IH, which was associated with decreased m(6)A levels in these cellsand tissues. Next, we knocked out ALKBH5 in a human lung adenocarcinoma cell lineunder IH, and we found that the proliferation and invasion of these cells weresignificantly inhibited. Mechanistic analysis showed that under IH, knockout ofALKBH5 in lung adenocarcinoma cells upregulated the level of m(6)A in Forkhead boxM1 (FOXM1) mRNA and decreased the translation efficiency of FOXM1 mRNA, resulting indownregulation of the FOXM1 protein. The FOXM1 protein is elevated in lungadenocarcinoma cells and subcutaneous tumor tissues of mice under IH. By knockingout FOXM1 in lung adenocarcinoma cells under IH, proliferation and invasion of thesecells were inhibited, and overexpression of FOXM1 partially restored the inhibitionof growth and invasion of lung adenocarcinoma cells due to ALKBH5 knockout.Collectively, our findings demonstrate that the m(6)A demethylase ALKBH5 affects theproliferation and invasion of lung adenocarcinoma cells under IH by downregulatingm(6)A modification on FOXM1 mRNA and by promoting FOXM1 expression.CI - Copyright © 2019 Elsevier Inc. All rights reserved.