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The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma
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The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma
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The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma
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Journal Article
The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma
2022
Overview
Background
N6-methyladenosine (m6A) RNA modification plays a critical role in various physiological and pathological conditions. However, the role of m6A modification in head and neck squamous cell carcinoma (HNSCC) remains elusive.
Methods
In this study, the expression of m6A demethylases was detected by HNSCC tissue microarray. m6A-RNA immunoprecipitation (MeRIP) sequencing and RNA sequencing were used to identify downstream targets of ALKBH5. Comprehensive identification of RNA-binding proteins by mass spectrometry (ChIRP-MS) was used to explore the m6A “readers”. Tumor-infiltrating lymphocytes were analyzed in SCC7-bearing xenografts in C3H mice.
Results
Here, we demonstrate the downregulation of m6A status and upregulation of two demethylases in HNSCC. Silencing the m6A demethylase alkB homolog 5, RNA demethylase (ALKBH5) suppresses tumor progression
in vitro
and
in vivo
. m6A-RNA immunoprecipitation sequencing reveals that ALKBH5 downregulates the m6A modification of
DDX58
mRNA. Moreover, RIG-I, encoded by the
DDX58
mRNA, reverses the protumorigenic characteristics of ALKBH5. ChIRP-MS demonstrates that HNRNPC binds to the m6A sites of
DDX58
mRNA to promote its maturation. ALKBH5 overexpression inhibits RIG-I-mediated IFNα secretion through the IKKε/TBK1/IRF3 pathway. The number of tumor-infiltrating lymphocytes in C3H immunocompetent mice is reduced by ALKBH5 overexpression and restored by IFNα administration. Upregulation of AKLBH5 negatively correlates with RIG-I and IFNα expression in HNSCC patients.
Conclusions
These findings unveil a novel mechanism of immune microenvironment regulation mediated by m6A modification through the ALKBH5/RIG-I/IFNα axis, providing a rationale for therapeutically targeting epitranscriptomic modulators in HNSCC.
Publisher
BioMed Central,Springer Nature B.V,BMC
Subject
AlkB Homolog 5, RNA Demethylase - genetics
/ AlkB Homolog 5, RNA Demethylase - metabolism
/ ALKBH5
/ Animals
/ Biomedical and Life Sciences
/ Cancer
/ Head and Neck Neoplasms - genetics
/ Head and neck squamous cell carcinoma
/ Humans
/ I-kappa B Kinase - metabolism
/ Interferon regulatory factor 3
/ Interferon Regulatory Factor-3 - metabolism
/ Mice
/ mRNA
/ Oncology
/ Protein Serine-Threonine Kinases - genetics
/ Proteins
/ RIG-I
/ Squamous Cell Carcinoma of Head and Neck - genetics
