The Biological Function, Mechanism, and Clinical Significance of m6A RNA Modifications in Head and Neck Carcinoma: A Systematic Review
31 May 2021-Frontiers in Cell and Developmental Biology (Front Cell Dev Biol)-Vol. 9, pp 683254-683254
TL;DR: In this article, the role of m6A modification in various types of head and neck squamous cell carcinoma (HNSCC) was discussed, and the development of potential targets for treating cancer based on the regulatory functions of m 6A, with an aim to improving targeted therapies for HNSCC.
Abstract: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers, yet the molecular mechanisms underlying its onset and development have not yet been fully elucidated. Indeed, an in-depth understanding of the potential molecular mechanisms underlying HNSCC oncogenesis may aid the development of better treatment strategies. Recent epigenetic studies have revealed that the m6A RNA modification plays important roles in HNSCC. In this review, we summarize the role of m6A modification in various types of HNSCC, including thyroid, nasopharyngeal, hypopharyngeal squamous cell, and oral carcinoma. In addition, we discuss the regulatory roles of m6A in immune cells within the tumor microenvironment, as well as the potential molecular mechanisms. Finally, we review the development of potential targets for treating cancer based on the regulatory functions of m6A, with an aim to improving targeted therapies for HNSCC. Together, this review highlights the important roles that m6A modification plays in RNA synthesis, transport, and translation, and demonstrates that the regulation of m6A-related proteins can indirectly affect mRNA and ncRNA function, thus providing a novel strategy for reengineering intrinsic cell activity and developing simpler interventions to treat HNSCC.
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TL;DR: Wang et al. as mentioned in this paper demonstrated that 13 of 19 m6A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19m6A regulatory genes in oral squamous cell carcinoma (OSCC).
Abstract: N6-methyladenosine (m6A) modification is the most prevalent modification on eukaryotic RNA, and the m6A modification regulators were involved in the progression of various cancers. However, the functions of m6A regulators in oral squamous cell carcinoma (OSCC) remain poorly understood. In this study, we demonstrated that 13 of 19 m6A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19 m6A regulatory genes in OSCC. Moreover, HNRNPA2B1 expression is elevated in OSCC, and a high level of HNRNPA2B1 is significantly associated with poor overall survival in OSCC patients. Functional studies, combined with further analysis of the correlation between the expression of HNRNPA2B1 and the EMT-related markers from the TCGA database, reveal that silencing HNRNPA2B1 suppresses the proliferation, migration, and invasion of OSCC via EMT. Collectively, our work shows that HNRNPA2B1 may have the potential to promote carcinogenesis of OSCC by targeting EMT via the LINE-1/TGF-β1/Smad2/Slug signaling pathway and provide insight into the critical roles of HNRNPA2B1 in OSCC.
21 citations
TL;DR: Wang et al. as discussed by the authors used multivariate cox regression to construct a risk model for lung squamous cell carcinoma (LUSC) patients, which was validated using Kaplan Meier survival analysis, receiver operating curve (ROC), and the correlations between the risk score and various immune cells infiltration were analyzed using various methods.
Abstract: Background: m6A-related lncRNAs emerged as potential targets for tumor diagnosis and treatment. This study aimed to identify m6A-regulated lncRNAs in lung squamous cell carcinoma (LUSC) patients. Material and methods: RNA-sequencing and clinical data of LUSC patients were downloaded from the Cancer Genome Atlas (TCGA) database. m6A-related lncRNAs were identified by using Pearson correlation assay. Univariate the multivariate cox regression analyses were utilized to construct a risk model. The performance of the risk model was validated using Kaplan Meier survival analysis, receiver operating curve (ROC). Immune estimation of LUSC were downloaded from TIMER. And the correlations between the risk score and various immune cells infiltration were analyzed using various methods. Differences in immune functions, and expression of immune checkpoint inhibitors and m6A regulators between high risk and low risk groups were further explored. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were utilized to explore the biological functions of AL122125.1. Results: A total of 351 m6A-related lncRNAs were obtained from TCGA. Seven lncRNAs demonstrated prognostic values. Further multivariate cox regression assay constructed a risk model consisted of 2 lncRNAs (AL122125.1 and HORMAD2-AS1). Kaplan-Meier analysis and area under the curve (AUC) indicated that this risk model could be used to predict the prognosis of LUSC patients. The m6A-retaed lncRNAs were immune associated. There were significant correlations between risk score and immune cell infiltration, immune functions and expression of immune checkpoint inhibitors. Meanwhile, there were significant differences in the expression of m6A regulators between the high- and low-risk groups. Moreover, GO and KEGG analyses revealed that upregulated expression of AL122125.1 was tumor-related. Conclusion: In this study, we constructed a m6A-related lncRNA risk model to predict the survival of LUSC patients. This study could provide novel insight to the prognosis and treatment of LUSC patients.
10 citations
TL;DR: The data reveal that immune cell infiltration, genetic mutation, and survival potential in OSCC patients are linked to m6A/m1A/ m5C/m7G/m6Am/Ψ-related genes, and a dependable prognostic model is constructed for OS CC patients.
Abstract: OBJECTIVES
To determine whether m6A/m1A/m5C/m7G/m6Am/Ψ-related genes influence the prognosis of a patient with oral squamous cell carcinoma.
MATERIALS AND METHODS
We investigated the changes in regulatory genes using publicly available data from The Cancer Genome Atlas. Consensus clustering by RNA methylation-related regulators was used to describe oral squamous cell carcinomas (OSCCs). Then we developed the prediction model. The tumor microenvironment was investigated using ESTIMATE. Gene set enrichment analysis was used to determine whether pathways or cell types were enriched in different groups. The association between the model and immune-related risk scores was investigated using correlation analysis.
RESULTS
We found 22 gene signatures in this analysis and then developed a predictive model that reveals the genes that are highly connected to the overall survival of OSCC patients. The survival and death rates were substantially different in the two groups (high and low risk) classified by the risk scores. The validation cohort verified the phenotypic diversity and prognostic effects of these genes.
CONCLUSION
Our data reveal that immune cell infiltration, genetic mutation, and survival potential in OSCC patients are linked to m6A/m1A/m5C/m7G/m6Am/Ψ-related genes, and we constructed a dependable prognostic model for OSCC patients.
5 citations
TL;DR: In this article , the authors highlight the numerous roles played by specific RNA-binding effectors in mediating post-transcriptional control of gene expression to shape the innate immunity.
Abstract: Innate immunity is the frontline of defense against infections and tissue damage. It is a fast and semi-specific response involving a myriad of processes essential for protecting the organism. These reactions promote the clearance of danger by activating, among others, an inflammatory response, the complement cascade and by recruiting the adaptive immunity. Any disequilibrium in this functional balance can lead to either inflammation-mediated tissue damage or defense inefficiency. A dynamic and coordinated gene expression program lies at the heart of the innate immune response. This expression program varies depending on the cell-type and the specific danger signal encountered by the cell and involves multiple layers of regulation. While these are achieved mainly via transcriptional control of gene expression, numerous post-transcriptional regulatory pathways involving RNA-binding proteins (RBPs) and other effectors play a critical role in its fine-tuning. Alternative splicing, translational control and mRNA stability have been shown to be tightly regulated during the innate immune response and participate in modulating gene expression in a global or gene specific manner. More recently, microRNAs assisting RBPs and post-transcriptional modification of RNA bases are also emerging as essential players of the innate immune process. In this review, we highlight the numerous roles played by specific RNA-binding effectors in mediating post-transcriptional control of gene expression to shape innate immunity.
5 citations
TL;DR: In this article , the authors analyzed the transcriptomes of 5902 single cells from a single-cell RNA-sequencing (scRNA-seq) dataset and found that multiple pathways are significantly enriched in HNSCC development including extracellular matrix structural components, humoral immune responses, and muscle contraction.
Abstract: The mechanism underlying the association between the development of head and neck squamous cell carcinoma (HNSCC) and ferroptosis is unclear. We analyzed the transcriptomes of 5902 single cells from a single-cell RNA-sequencing (scRNA-seq) dataset. They then aggregate into B cells, epithelial cells, fibroblasts, germ cells, mesenchymal cells, cancer stem cells, stem cells, T cells and endometrial cells, respectively. Our study shows that multiple pathways are significantly enriched in HNSCC development including extracellular matrix structural components, humoral immune responses, and muscle contraction. Differentially expressed genes analysis in Pseudotime analysis, pathway and biological function indicated that there was a significant correlation in the ferroptosis pathway. Furthermore, higher ferroptosis potential index (FPI) scores were significantly associated with worse overall survival prognosis in HNSCC patients. Pseudo-temporal, survival analyses and immunohistochemistry identified multiple central genes in HNSCC development, including ACSL1, SLC39A14, TFRC, and PRNP genes, and indicated associated ferroptosis. Overall, our study detected ferroptosis-related features is closely correlated with HNSCC prognosis and development, and deserved candidates suitable for immunotherapy treatment strategies determination for HNSCC patients.
2 citations
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TL;DR: The findings suggest that RNA decoration by m6A has a fundamental role in regulation of gene expression, and a subset of stimulus-dependent, dynamically modulated sites is identified.
Abstract: An extensive repertoire of modifications is known to underlie the versatile coding, structural and catalytic functions of RNA, but it remains largely uncharted territory. Although biochemical studies indicate that N(6)-methyladenosine (m(6)A) is the most prevalent internal modification in messenger RNA, an in-depth study of its distribution and functions has been impeded by a lack of robust analytical methods. Here we present the human and mouse m(6)A modification landscape in a transcriptome-wide manner, using a novel approach, m(6)A-seq, based on antibody-mediated capture and massively parallel sequencing. We identify over 12,000 m(6)A sites characterized by a typical consensus in the transcripts of more than 7,000 human genes. Sites preferentially appear in two distinct landmarks--around stop codons and within long internal exons--and are highly conserved between human and mouse. Although most sites are well preserved across normal and cancerous tissues and in response to various stimuli, a subset of stimulus-dependent, dynamically modulated sites is identified. Silencing the m(6)A methyltransferase significantly affects gene expression and alternative splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. Our findings therefore suggest that RNA decoration by m(6)A has a fundamental role in regulation of gene expression.
3,237 citations
TL;DR: It is shown that m6A is selectively recognized by the human YTH domain family 2 (YTHDF2) ‘reader’ protein to regulate mRNA degradation and established the role of YTH DF2 in RNA metabolism, showing that binding of Y THDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies.
Abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.
2,699 citations
TL;DR: FTO exhibits efficient oxidative demethylation activity of abundant N6-methyladenosine (m6A) residues in RNA in vitro, and it is shown that FTO partially colocalizes with nuclear speckles, supporting m6A in nuclear RNA as a physiological substrate of FTO.
Abstract: We report here that fat mass and obesity-associated protein (FTO) has efficient oxidative demethylation activity targeting the abundant N6-methyladenosine (m(6)A) residues in RNA in vitro. FTO knockdown with siRNA led to increased amounts of m(6)A in mRNA, whereas overexpression of FTO resulted in decreased amounts of m(6)A in human cells. We further show the partial colocalization of FTO with nuclear speckles, which supports the notion that m(6)A in nuclear RNA is a major physiological substrate of FTO.
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TL;DR: This work has provided a solid foundation for studying the regulation of translation initiation by mechanisms that include the modulation of initiation factor activity and through sequence-specific RNA-binding proteins and microRNAs (which affect individual mRNAs).
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2,446 citations