The N(6)-methyladenosine (m6A) modification is the most pervasive modification of human RNAs. In recent years, an increasing number of studies have suggested that m6A likely plays important roles in cancers. Many studies have demonstrated that m6A is involved in the biological functions of cancer cells, such as proliferation, invasion, metastasis, and drug resistance. In addition, m6A is closely related to the prognosis of cancer patients. In this review, we highlight recent advances in understanding the function of m6A in various cancers. We emphasize the importance of m6A to cancer progression and look forward to describe future research directions. 

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Role of m6A writers, erasers and readers in cancer

Background: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies.

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

Accumulating evidence has revealed that m6A modification, the predominant RNA modification in eukaryotes, adds a novel layer of regulation to the gene expression. Dynamic and reversible m6A modification implements sophisticated and crucial functions in RNA metabolism, including generation, splicing, stability, and translation in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs). Furthermore, m6A modification plays a determining role in producing various m6A-labeling RNA outcomes, thereby affecting several functional processes, including tumorigenesis and progression. Herein, we highlighted current advances in m6A modification and the regulatory mechanisms underlying mRNAs and ncRNAs in distinct cancer stages. Meanwhile, we also focused on the therapeutic significance of m6A regulators in clinical cancer treatment.

Novel insights into m6A modification of coding and non-coding RNAs in tumor biology: From molecular mechanisms to therapeutic significance

ABSTRACT The last decade has seen mRNA modification emerge as a new layer of gene expression regulation. The Fat mass and obesity-associated protein (FTO) was the first identified eraser of N6-methyladenosine (m6A) adducts, the most widespread modification in eukaryotic messenger RNA. This discovery, of a reversible and dynamic RNA modification, aided by recent technological advances in RNA mass spectrometry and sequencing has led to the birth of the field of epitranscriptomics. FTO crystallized much of the attention of epitranscriptomics researchers and resulted in the publication of numerous, yet contradictory, studies describing the regulatory role of FTO in gene expression and central biological processes. These incongruities may be explained by a wide spectrum of FTO substrates and RNA sequence preferences: FTO binds multiple RNA species (mRNA, snRNA and tRNA) and can demethylate internal m6A in mRNA and snRNA, N6,2′-O-dimethyladenosine (m6Am) adjacent to the mRNA cap, and N1-methyladenosine (m1A) in tRNA. Here, we review current knowledge related to FTO function in healthy and cancer cells. In particular, we emphasize the divergent role(s) attributed to FTO in different tissues and subcellular and molecular contexts.

https://www.tandfonline.com/doi/pdf/10.1080/15476286.2021.2016203?needAccess=true

The multifaceted functions of the Fat mass and Obesity-associated protein (FTO) in normal and cancer cells

N6-methyladenosine (m6A) RNA methylation has been considered the most prevalent, abundant, and conserved internal transcriptional modification throughout the eukaryotic mRNAs. Typically, m6A RNA methylation is catalyzed by the RNA methyltransferases (writers), is removed by its demethylases (erasers), and interacts with m6A-binding proteins (readers). Accumulating evidence shows that abnormal changes in the m6A levels of these regulators are increasingly associated with human tumorigenesis and drug resistance. However, the molecular mechanisms underlying m6A RNA methylation in tumor occurrence and development have not been comprehensively clarified. We reviewed the recent findings on biological regulation of m6A RNA methylation and summarized its potential therapeutic strategies in various human cancers.

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The Emerging Role of N6-Methyladenosine RNA Methylation as Regulators in Cancer Therapy and Drug Resistance

m6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non-small cell lung cancer.

Background In this study, we aimed to identify the pathogenesis and prognostic biomarkers of lung adenocarcinoma (LUAD). Methods Differentially expressed mRNAs (DEmRNAs) and single nucleotide polymorphism (SNP) mutant genes were screened. In addition, enrichment and protein-protein interaction (PPI) network analyses of the SNP-mutated genes were performed. Thereafter, the correlation between gene mutation and expression was analyzed. Finally, the mutated genes associated with LUAD prognosis were validated on the basis of The Cancer Genome Atlas (TCGA) database. Results A total of 2502 DEmRNAs were initially screened in this study. We identified 756 SNP-mutated genes from more than 30 cases. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the mutated genes involved in LUAD were mainly associated with the ECM-receptor interaction, focal adhesion, and calcium signaling pathways. Tumor protein p53 (TP53) and neurexin 1 (NRXN1) with the higher degree were chosen as the hub genes in the PPI network. In addition, the correlation analysis revealed six genes, including assembly factor for spindle microtubules (ASPM), centromere protein F (CENPF), contactin 3 (CNTN3), catenin delta 2 (CTNND2), PKHD1 like 1 (PKHD1L1), and semaphorin 6D (SEMA6D), and three SNP mutations at ASPM rs368020495, CENPF rs762653487, and PKHD1L1 rs768349010 sites that were found to be associated with LUAD prognosis. Further validation showed that among the aforementioned six mutated genes, CENPF was upregulated and SEMA6D was downregulated. Conclusion CENPF, SEMA6D, TP53, and NRXN1 were found to be closely associated with the development of LUAD.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcla.23450

Screening and identification of biomarkers associated with the diagnosis and prognosis of lung adenocarcinoma.

The significance of epigenetic modulation, involving acetylation, methylation, as well as ubiquitination has been indicated in the regulation of gene expression and tumor progression. Here, we elucidated the role of histone deacetylase 6 (HDAC6) in regulating epithelial-mesenchymal transition (EMT)-mediated metastasis via mRNA in non-small cell lung cancer (NSCLC). Three microarrays associated with lung cancer metastasis or recurrence, GSE23361, GSE7880 and GSE162102, were downloaded from the GEO database. Transmembrane protein 100 (TMEM100) was revealed to be the only one mRNA that was significantly downregulated in three microarrays. TMEM100, poorly expressed in lung cancer tissues, was associated with poor prognosis of lung cancer patients. Moreover, TMEM100 transcription was regulated by HDAC6 which repressed TMEM100 expression by deacetylation modification on the TMEM100 promoter. Knockdown of HDAC6 or overexpression of TMEM100 in NSCLC cells significantly inhibited TGF-β1-induced EMT and metastasis and suppressed the activation of Wnt/β-catenin signaling pathway. Altogether, our study highlights HDAC6 as a lung cancer metastasis supporter through the suppression of TMEM100 and the induction of Wnt/β-catenin signaling pathway.

Yitong Chen

Papers

m6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non-small cell lung cancer.

Screening and identification of biomarkers associated with the diagnosis and prognosis of lung adenocarcinoma.

Histone deacetylase 6-mediated downregulation of TMEM100 expedites the development and progression of non-small cell lung cancer.