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Updated: Nov 22, 2025
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
ALKBH5-mediated m6A demethylation of FOXM1 mRNA promotes progression of uveal melanoma
Lili Hao1, Jiayang Yin1, Hong Yang1
1Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong Province, China.
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.
Insights
ALKBH5, a key protein in N6-methyladenosine modification, is elevated in uveal melanoma (UM). Lowering ALKBH5 inhibits UM tumor growth and metastasis, identifying it as a potential therapeutic target.
Area of Science:
- Molecular Oncology
- Epigenetics
- Ophthalmology
Background:
- Uveal melanoma (UM) is the most common primary intraocular malignancy in adults.
- The role of epitranscriptomic modifications, such as N6-methyladenosine (m6A), in UM progression is increasingly recognized.
- ALKBH5, an m6A demethylase, has been implicated in various cancers, but its specific role in UM requires further elucidation.
Purpose of the Study:
- To investigate the role of ALKBH5 in the development and progression of uveal melanoma.
- To explore the underlying molecular mechanisms by which ALKBH5 influences UM.
- To evaluate ALKBH5 as a potential prognostic biomarker and therapeutic target for UM.
Main Methods:
- Analysis of ALKBH5 expression in UM cell lines and patient data.
- In vivo and in vitro experiments involving ALKBH5 knockdown and overexpression.
- Investigation of the interaction between ALKBH5, H3K27 acetylation, and FOXM1 mRNA stability.
Main Results:
- ALKBH5 was significantly upregulated in UM cell lines and associated with poor patient outcomes.
- Downregulation of ALKBH5 suppressed UM cell proliferation, migration, invasion, and induced apoptosis in vitro, and inhibited tumor growth in vivo.
- ALKBH5 promotes UM metastasis by demethylating FOXM1 mRNA, enhancing its expression and stability, potentially via EP300-induced H3K27 acetylation.
Conclusions:
- ALKBH5 plays a critical oncogenic role in uveal melanoma progression and metastasis.
- The m6A demethylase ALKBH5 targets FOXM1 mRNA, contributing to UM aggressiveness.
- ALKBH5 represents a promising prognostic biomarker and a potential therapeutic target for uveal melanoma.
