ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer

Jan 12, 2023Theranostics

ALKBH5 increases tumor lymph vessel growth and spread to lymph nodes in ovarian cancer by activating FAK signaling through m6A removal in ITGB1 RNA

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

m6A modification levels were reduced in ovarian cancers with lymph node (LN) metastases.

Lymph node metastasis is common in patients with epithelial ovarian cancer and is associated with poor prognosis.
ALKBH5 overexpression is linked to increased tumor-associated lymphangiogenesis and LN metastasis.
ALKBH5 overexpression reverses m6A modification in mRNA, leading to increased expression of ITGB1 and activation of FAK and Src proteins.
Hypoxia induces expression of a specific factor that enhances ALKBH5 expression and promotes LN metastasis in epithelial ovarian cancer.
The ALKBH5/m6A-ITGB1/FAK signaling axis may play a crucial role in lymphangiogenesis and LN metastasis in ovarian cancer.

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Lymph node (LN) metastasis is common in patients with epithelial ovarian cancer (EOC) and is associated with poor prognosis. Tumor-associated lymphangiogenesis is the first stage of LN metastasis. Research on lymphangiogenesis and lymph node metastases can help develop new anti-LN-targeted therapies. Aberrant N6-methyladenosine (m6A) modifications have been reported to be linked to LN metastasis in several cancers, however, their role in EOC lymphangiogenesis and LN metastasis remains unclear.m6A levels in EOC tissues with or without LN metastases were evaluated by dot blot analysis. Real-time polymerase chain reaction (PCR) and immunofluorescence were used to examine the expression of m6A-related enzymes. Additionally,andfunctional studies were performed to discover the importance of the AlkB homolog 5 () gene in EOC lymphatic metastasis. To identify the downstream target genes regulated by ALKBH5, we performed RNA pulldown, RNA-binding protein immunoprecipitation-quantitative PCR, co-immunoprecipitation, m6A-modified RNA immunoprecipitation-quantitative PCR, and luciferase reporter assays.m6A modification was reduced in ovarian cancers with LN metastases. ALKBH5 overexpression increased tumor-associated lymphangiogenesis and LN metastasis bothand. ALKBH5 overexpression also reversed the m6A modification inmRNA and suppressed the YTHDF2 protein-mediated m6A-dependentmRNA degradation, which resulted in increased expression of ITGB1 and phosphorylation of the focal adhesion kinase (FAK) and Src proto-oncogene proteins, thereby increasing LN metastasis. Furthermore, hypoxia induced the expression of hypoxia inducible factor 1 subunit alpha, which increased ALKBH5 expression and enhanced LN metastasis in EOC.The ALKBH5/m6A-ITGB1/FAK signalling axis is important in ovarian cancer lymphangiogenesis and LN metastasis. Antibodies that block ITGB1 and FAK kinase-inhibitors are promising anti-metastatic agents. Background: Methods: Results: Conclusions: in vitro in vivo ALKBH5in vitro in vivo ITGB1ITGB1

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ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer

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