Abstract
As a critical internal RNA modification in higher eukaryotes, N6-methyladenosine (m6A) has become the hotspot of epigenetics research in recent years. Extensive studies on messenger RNAs have revealed that m6A affects RNA fate and cell functions in various bioprocesses, such as RNA splicing, export, translation, and stability, some of which seem to be directly or indirectly regulated by noncoding RNAs. Intriguingly, abundant noncoding RNAs such as microRNAs, long noncoding RNAs, circular RNAs, small nuclear RNAs, and ribosomal RNAs are also highly modified with m6A and require m6A modification for their biogenesis and functions. Here, we discuss the interaction between m6A modification and noncoding RNAs by focusing on the functional relevance of m6A in cancer progression, metastasis, drug resistance, and immune response. Furthermore, the investigation of m6A regulatory proteins and its inhibitors provides new opportunities for early diagnosis and effective treatment of cancer, especially in combination with immunotherapy.
Highlights
N6-methyladenosine (m6A), first described in 1974 [1, 2], is a well-known internal modification of messenger RNAs and noncoding RNAs; it is widely conserved among eukaryotes ranging from yeast, plants, and flies to mammals and even occurs in viral RNAs with a nuclear phase [3, 4]
As the most abundant and important messenger RNAs (mRNAs) modification in mammals, m6A modification accounts for approximately 50% of the total methyl-labeled ribonucleosides [5] and 0.1–0.4% of all adenosines in total cellular RNAs with about 3–5 m6A sites per mRNA [6]. m6A is enriched in the consensus sequence RRACH and highly occurs in 3′ untranslated regions (3′-UTRs), stop codons, and internal long exons [4, 7], showing
In non-small cell lung cancer (NSCLC), methyltransferase-like 3 (METTL3)-mediated m6A modification increases the levels and stability of Metastasis-associated lung adenocarcinoma transcript (MALAT1), which acts as a competitive endogenous RNA (ceRNA) to abolish the gene silencing function of miR1914-3p, and thereby increases the downstream target YAP, leading to NSCLC metastasis and drug resistance to cisplatin [61]. These findings suggest the regulatory role of m6A in long noncodingRNAs (lncRNAs)-mediated ceRNA model related to cancer development and chemoresistance, and provides a new idea for cancer diagnosis and treatment
Summary
N6-methyladenosine (m6A), first described in 1974 [1, 2], is a well-known internal modification of messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs); it is widely conserved among eukaryotes ranging from yeast, plants, and flies to mammals and even occurs in viral RNAs with a nuclear phase [3, 4]. Roles of m6A methylation on ncRNAs in cancer MicroRNAs miRNAs are a class of noncoding single-stranded RNAs with a length of 21–25 nucleotides; they regulate gene expression at the post-transcriptional level by forming the RNA-induced silencing complex (RISC), which binds to the 3′-UTR of target mRNAs, resulting in either translational inhibition or mRNA degradation [31].
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