Dataset Information

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

ABSTRACT: Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m⁶A) RNA modification occurs in HPSCC. The expression of the m⁶A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferation by regulating human Toll-like receptor 2 (TLR2) in an m⁶A-dependent manner in HPSCC cells. ALKBH5 decreased TLR2 m⁶A modification, which could be recognized by the m⁶A readers IGF2BP2 and YTHDF1. IGF2BP2 facilitates TLR2 mRNA stability, whereas YTHDF1 promotes TLR2 mRNA translation. The current work uncovered a critical function of ALKBH5 in TLR2 regulation and provides a novel role for m⁶A demethylation of mRNA in HPSCC. The inhibition of m⁶A modification of ALKBH5 in HPSCC deserves further clinical investigation.

SUBMITTER: Ye J

PROVIDER: S-EPMC10447508 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

Ye Jing J Wu Yuting Y Chen Yao Y Ren Yiyue Y Jiang Xiaohua X Dong Zhihuai Z Zhang Jingna J Jin Mao M Chen Xiaozhen X Wang Zhanggui Z Xiao Mang M

Cell death discovery 20230823 1

Hypopharyngeal squamous cell carcinoma (HPSCC) is one of the most aggressive cancers and is notorious for its extremely poor prognosis. However, very few molecular biological studies have been performed. As a novel method of epigenetic gene modulation, N6-methyladenosine (m<sup>6</sup>A) RNA modification occurs in HPSCC. The expression of the m<sup>6</sup>A demethylase AlkB homolog 5 (ALKBH5) is frequently downregulated in human HPSCC. Furthermore, we found that ALKBH5 impaired cell proliferatio ...[more]

PMID: 37612282

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Project description:BackgroundN6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated.Methods The integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A "reader" protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein-protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation.ResultsOur study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1.ConclusionOur study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.

Project description:Background: N6-methyladenosine (m6A) is the most abundant internal modification pattern in mammals that a plays critical role in tumorigenesis and immune regulations. However, the effect of m6A modification on head and neck squamous cell carcinoma (HNSCC) has not been clearly studied. Methods: We screened m6A regulators that were significantly correlated with tumor immune status indicated by ImmuneScore using The Cancer Genome Atlas (TCGA) dataset and obtained distinct patient clusters based on the expression of these m6A regulators with the R package "CensusClusterPlus." We then performed gene set enrichment analysis (GSEA), CIBERSORT, and single-sample gene set enrichment analysis (ssGSEA) to assess the differences in gene function enrichment and tumor immune microenvironment (TIME) among these clusters. We further conducted differently expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) and constructed a protein-protein interaction (PPI) network to determine hub genes among these clusters. Finally, we used the GSE65858 dataset as an external validation cohort to confirm the immune profiles related to the expression of m6A regulators. Results: Two m6A readers, YTHDF1 and IGF2BP2, were found to be significantly associated with distinct immune status in HNSCC. Accordingly, patients were divided into two clusters with Cluster 1 showing high expression of YTHDF1 and IGF2BP2 and Cluster 2 showing low expression levels of both genes. Clinicopathologically, patients from Cluster 1 had more advanced T stage and pathological grades than those from Cluster 2. GSEA showed that Cluster 1 was closely related to the RNA modification process and Cluster 2 was significantly correlated with immune regulations. Cluster 2 had a more active TIME characterized by a more relative abundance of CD8+ T cells and CD4+ T cells and higher levels of MHC I and MHC II molecules. We constructed a PPI network composed of 16 hub genes between the two clusters, which participated in the T-cell receptor signaling pathway. These results were externally validated in the GSE65858 dataset. Conclusions: The m6A readers, YTHDF1 and IGF2BP2, were potential immune biomarkers in HNSCC and could be potential treatment targets for cancer immunotherapy.

Dataset Information

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

Publications

ALKBH5 promotes hypopharyngeal squamous cell carcinoma apoptosis by targeting TLR2 in a YTHDF1/IGF2BP2-mediated manner.

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