m6A demethylase ALKBH5 suppression contributes to esophageal squamous cell carcinoma progression.

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly malignant gastrointestinal cancer with a high recurrence rate and poor prognosis. Although N6-methyladenosine (m6A), the most abundant epitranscriptomic modification of mRNAs, has been implicated in several cancers, little is known about its participation in ESCC progression. We found reduced expression of ALKBH5, an m6A demethylase, in ESCC tissue specimens with a more pronounced effect in T3-T4, N1-N3, clinical stages III-IV, and histological grade III tumors, suggesting its involvement in advanced stages of ESCC. Exogenous expression of ALKBH5 inhibited the in vitro proliferation of ESCC cells, whereas depletion of endogenous ALKBH5 markedly enhanced ESCC cell proliferation in vitro. This suggests ALKBH5 exerts anti-proliferative effects on ESCC growth. Furthermore, ALKBH5 overexpression suppressed tumor growth of Eca-109 cells in nude mice; conversely, depletion of endogenous ALKBH5 accelerated tumor growth of TE-13 cells in vivo. The growth-inhibitory effects of ALKBH5 overexpression are partly attributed to a G1-phase arrest. In addition, ALKBH5 overexpression reduced the in vitro migration and invasion of ESCC cells. Altogether, our findings demonstrate that the loss of ALKBH5 expression contributes to ESCC malignancy.

• Authors: Dong Xiao, Ting-Xiao Fang, Ye Lei, Sheng-Jun Xiao, Jia-Wei Xia, Tao-Yan Lin, Yong-Long Li, Jian-Xue Zhai, Xiao-Yan Li, Shi-Hao Huang, Jun-Shuang Jia, Yu-Guang Tian, Xiao-Lin Lin, Kai-Can Cai, Yan Sun
• Journal: Aging (Aging (Albany NY)) Vol. 13 Issue 17 Pg. 21497-21512 (09 07 2021) ISSN: 1945-4589 [Electronic] United States
• PMID: 34491904 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• N-methyladenosine
• ALKBH5 protein, human
• AlkB Homolog 5, RNA Demethylase
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism)
• Adult
• Aged
• AlkB Homolog 5, RNA Demethylase (metabolism)
• Animals
• Carcinogenesis
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Esophageal Neoplasms (genetics, metabolism, pathology)
• Esophageal Squamous Cell Carcinoma (genetics, metabolism)
• Esophagus (metabolism, pathology)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Nude
• Middle Aged
• RNA Processing, Post-Transcriptional
• RNA, Messenger (metabolism)
• Xenograft Model Antitumor Assays
• Mice