Abstract
In this study, we found that ALKBH5, a key component of the N6-methyladenosine (m6A) methyltransferase complex, was significantly elevated in uveal melanoma (UM) cell lines and that ALKBH5 downregulation inhibited tumor growth in vivo. High ALKBH5 expression predicted worse outcome in patients with UM. EP300-induced H3K27 acetylation activation increased ALKBH5 expression. Downregulation of ALKBH5 inhibited UM cell proliferation, migration, and invasion and increased apoptosis in vitro. Besides, ALKBH5 may promote UM metastasis by inducing epithelial-to-mesenchymal transition (EMT) via demethylation of FOXM1 mRNA, which increases its expression and stability. In sum, our study indicates that AKLBH5-induced m6A demethylation of FOXM1 mRNA promotes UM progression. Therefore, AKLBH5 is a potential prognostic biomarker and therapeutic target in UM.
Keywords:
ALKBH5; FOXM1; m6A demethylation; uveal melanoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives*
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Adenosine / metabolism
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AlkB Homolog 5, RNA Demethylase / genetics*
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AlkB Homolog 5, RNA Demethylase / metabolism
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Animals
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Proliferation / genetics
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Demethylation
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Disease Progression
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Epithelial-Mesenchymal Transition / genetics
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Forkhead Box Protein M1 / genetics*
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Forkhead Box Protein M1 / metabolism
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Gene Expression Regulation, Neoplastic / genetics
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Humans
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Melanoma / genetics*
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Nude
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Neoplasm Transplantation
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RNA Processing, Post-Transcriptional / genetics
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RNA Stability
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RNA, Messenger / metabolism*
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Uveal Neoplasms / genetics*
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Uveal Neoplasms / metabolism
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Uveal Neoplasms / pathology
Substances
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FOXM1 protein, human
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Forkhead Box Protein M1
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RNA, Messenger
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N-methyladenosine
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ALKBH5 protein, human
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AlkB Homolog 5, RNA Demethylase
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Adenosine