ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia

Nov 4, 2019Biochemical and biophysical research communications

ALKBH5-m6A-FOXM1 pathway may increase lung cancer cell growth and spread during low oxygen episodes

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Abstract

ALKBH5 levels were elevated in lung adenocarcinoma cells under intermittent hypoxia (IH), which is associated with decreased mA levels.

Elevated ALKBH5 in lung adenocarcinoma cells correlates with lower mA levels.
Knocking out ALKBH5 in lung adenocarcinoma cells under IH significantly inhibits cell proliferation and invasion.
The knockout of ALKBH5 increases mA levels in FOXM1 mRNA, which leads to decreased translation efficiency of FOXM1.
FOXM1 protein is found to be elevated in lung adenocarcinoma cells and tumors under IH.
Knocking out FOXM1 reduces proliferation and invasion of lung adenocarcinoma cells, while its overexpression can partially reverse the effects of ALKBH5 knockout.

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Obstructive sleep apnea (OSA) is closely associated with cancer progression and cancer-related mortality. N6-methyladenosine (mA) is involved in the process of intermittent hypoxia (IH) promoting tumor progression. However, it is unclear how mA regulates the development of lung adenocarcinoma under IH. In this study, we found that ALKBH5 was elevated in lung adenocarcinoma cells and subcutaneous tumors in mice under IH, which was associated with decreased mA levels in these cells and tissues. Next, we knocked out ALKBH5 in a human lung adenocarcinoma cell line under IH, and we found that the proliferation and invasion of these cells were significantly inhibited. Mechanistic analysis showed that under IH, knockout of ALKBH5 in lung adenocarcinoma cells upregulated the level of mA in Forkhead box M1 (FOXM1) mRNA and decreased the translation efficiency of FOXM1 mRNA, resulting in downregulation of the FOXM1 protein. The FOXM1 protein is elevated in lung adenocarcinoma cells and subcutaneous tumor tissues of mice under IH. By knocking out FOXM1 in lung adenocarcinoma cells under IH, proliferation and invasion of these cells were inhibited, and overexpression of FOXM1 partially restored the inhibition of growth and invasion of lung adenocarcinoma cells due to ALKBH5 knockout. Collectively, our findings demonstrate that the mA demethylase ALKBH5 affects the proliferation and invasion of lung adenocarcinoma cells under IH by downregulating mA modification on FOXM1 mRNA and by promoting FOXM1 expression. 6 6 6 6 6 6

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ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia

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