m⁶A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis

May 26, 2020Genes to cells : devoted to molecular & cellular mechanisms

ALKBH5 enzyme increases growth of esophageal squamous cell cancer linked to worse outcomes

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Abstract

Higher expression of the mA demethylase ALKBH5 in tumors from 177 esophageal squamous cell carcinoma patients is associated with poor prognosis.

ALKBH5 is identified as an independent prognostic factor for survival in ESCC patients.
Knockdown of ALKBH5 significantly suppresses proliferation and migration of human ESCC cells.
Depletion of ALKBH5 leads to cell cycle arrest in the G0/G1 phase.
Expression of the cell cycle regulator CDKN1A (p21) is significantly increased when ALKBH5 is knocked down.
ALKBH5 knockdown enhances the mA modification and stability of CDKN1A mRNA.
In vivo studies show that depletion of ALKBH5 significantly suppresses tumor growth in mice.

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Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N-methyladenosine (mA) of mRNA, is an abundant post-transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of mA modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of mA demethylase ALKBH5 correlated with poor prognosis and that ALKBH5 was an independent prognostic factor of the survival of patients. There was no correlation between the other demethylase FTO and prognosis. siRNA knockdown of ALKBH5 but not FTO significantly suppressed proliferation and migration of human ESCC cells. ALKBH5 knockdown delayed progression of cell cycle and accumulated the cells to G0/G1 phase. Mechanistically, expression of CDKN1A (p21) was significantly up-regulated in ALKBH5-depleted cells, and mA modification and stability of CDKN1A mRNA were increased by ALKBH5 knockdown. Furthermore, depletion of ALKBH5 substantially suppressed tumor growth of ESCC cells subcutaneously transplanted in BALB/c nude mice. Collectively, we identify ALKBH5 as the first mA demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients. 6 6 6 6 6 6

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m⁶A demethylase ALKBH5 promotes proliferation of esophageal squamous cell carcinoma associated with poor prognosis

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