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

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most fatal types of malignant tumors worldwide. Epitranscriptome, such as N6‐methyladenosine (m6A) of mRNA, is an abundant post‐transcriptional mRNA modification and has been recently implicated to play roles in several cancers, whereas the significance of m6A modifications is virtually unknown in ESCC. Analysis of tissue microarray of the tumors in 177 ESCC patients showed that higher expression of m6A 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 m6A 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 m6A demethylase that accelerates cell cycle progression and promotes cell proliferation of ESCC cells, which is associated with poor prognosis of ESCC patients.

Identification of a m6A RNA methylation regulators-based signature for predicting the prognosis of esophageal adenocarcinoma

“…Among the 5 genes, ALKBH5 was the only protective gene for the prognosis of EAC. Nonetheless, a previous study investigated the association between ALKBH5 and prognosis in 177 patients with ESCC, and identi ed ALKBH5 as the rst demethylase that accelerated cell cycle progression and promoted cell proliferation of ESCC cells, suggesting that the up-regulation of ALKBH5 was associated with poor prognosis in ESCC [35]. Conversely, ALKBH5 has been reported to inhibit pancreatic cancer motility by demethylating lncRNA KCNK15-AS1 [43], which agrees with the result in our study to some extent.…”

“…Esophageal cancer is one of the most aggressive malignant tumors with two main histological subtypes, EAC and ESCC. Several studies have explored the association between m 6 A modi cations and ESCC [28,34,35];…”

N6-methyladenosine (m6A) RNA methylation signature as a predictor of stomach adenocarcinoma outcomes and its association with immune checkpoint molecules

“…Effectors including RBM15, ALKBH5, and YTHDF2 can regulate the cell cycle biological process. 34 – 36 Another study similarly reported that YTHDF2 mediated the degradation of RNAs containing m 6 A in mammals. 37 However, the involvement of m 6 A in DNA mismatch repair has not previously been reported; this relationship is a potential avenue for future research.…”

Recent advances of m6A methylation modification in esophageal squamous cell carcinoma

“…Functional analysis showed that ALKBH5 could inhibit the proliferation, migration and invasion of EC cells. However, a recent study found that ALKBH5 promotes the proliferation and migration of ESCC [ 27 ]. These results contradict previous findings.…”