Dysregulations of Functional RNA Modifications in Cancer, Cancer Stemness and Cancer Therapeutics.
TL;DR: It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood and further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.
Abstract: More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far. Many of the RNA modifications are dynamic and reversible, playing critical roles in gene regulation at the posttranscriptional level. The abundance and functions of RNA modifications are controlled mainly by the modification regulatory proteins: writers, erasers and readers. Modified RNA bases and their regulators form intricate networks which are associated with a vast array of diverse biological functions. RNA modifications are not only essential for maintaining the stability and structural integrity of the RNA molecules themselves, they are also associated with the functional outcomes and phenotypic attributes of cells. In addition to their normal biological roles, many of the RNA modifications also play important roles in various diseases particularly in cancer as evidenced that the modified RNA transcripts and their regulatory proteins are aberrantly expressed in many cancer types. This review will first summarize the most commonly reported RNA modifications and their regulations, followed by discussing recent studies on the roles of RNA modifications in cancer, cancer stemness as wells as functional RNA modification machinery as potential cancer therapeutic targets. It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood. Moreover, whether and how environmental pollutants, important cancer etiological factors, trigger abnormal RNA modifications and their roles in environmental carcinogenesis remain largely unknown. Further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.
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TL;DR: The m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes Dysregulations due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms as discussed by the authors.
Abstract: The m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer
53 citations
TL;DR: In this article , the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research, which refers to heritable modifications in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes.
Abstract: Abstract Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in the genetic material without any changes in the nucleic acid sequence and results in heritable phenotypic changes. Epigenetic modifications regulate many biological processes, such as growth, aging, and various diseases, including cancer. With the advancement of next-generation sequencing technology, the role of RNA modifications in cancer progression has become increasingly prominent and is a hot spot in scientific research. This review studied several common RNA modifications, such as N 6 -methyladenosine, 5-methylcytosine, and pseudouridine. The deposition and roles of these modifications in coding and noncoding RNAs are summarized in detail. Based on the RNA modification background, this review summarized the expression, function, and underlying molecular mechanism of these modifications and their regulators in cancer and further discussed the role of some existing small-molecule inhibitors. More in-depth studies on RNA modification and cancer are needed to broaden the understanding of epigenetics and cancer diagnosis, treatment, and prognosis.
36 citations
TL;DR: The role of RNA modifications in response to these cellular stressors is context-and cell-type-dependent as mentioned in this paper, and they have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases.
Abstract: RNA modifications are diverse post-transcriptional modifications that regulate RNA metabolism and gene expression. RNA modifications, and the writers, erasers, and readers that catalyze these modifications, serve as important signaling machineries in cellular stress responses and disease pathogenesis. In response to stress, RNA modifications are mobilized to activate or inhibit the signaling pathways that combat stresses, including oxidative stress, hypoxia, therapeutic stress, metabolic stress, heat shock, DNA damage, and ER stress. The role of RNA modifications in response to these cellular stressors is context- and cell-type-dependent. Due to their pervasive roles in cell biology, RNA modifications have been implicated in the pathogenesis of different diseases, including cancer, neurologic and developmental disorders and diseases, and metabolic diseases. In this review, we aim to summarize the roles of RNA modifications in molecular and cellular stress responses and diseases.
27 citations
TL;DR: In this paper, the role of RNA methylation in the pathophysiology of CVDs and the potential of using epigenetics to treat such disorders was summarized, and several approaches have been proposed for the prevention and treatment of cardiovascular diseases.
20 citations
TL;DR: Wang et al. as discussed by the authors carried out the comprehensive profiling and evaluation of the alteration of RNA modifications in thyroid carcinoma by liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) analysis.
19 citations
References
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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
"Dysregulations of Functional RNA Mo..." refers background in this paper
...These proteins were identified for the first time using the antibodies targeting the methylated RNA and co-immunoprecipitation followed by mass spectrometry analysis [24]....
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...In 2012 two research groups independently described the methods to determine the genome-wide distribution of m6A methylated mRNA [9, 24]....
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TL;DR: A method is presented for transcriptome-wide m(6)A localization, which combines m( 6)A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-Seq) and reveals insights into the epigenetic regulation of the mammalian transcriptome.
2,839 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.
2,647 citations
"Dysregulations of Functional RNA Mo..." refers background in this paper
...Like their methylating counter parts METTL3 and METTL14, FTO also co-localizes with them in the nuclear speckles which emphasizes the dynamicity and reversibility of the m6A modification process in mRNA [13]....
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...The demethylating ALKB enzyme family recognizes the methylation on adenine and cytosine nucleotide bases in both single stranded DNA and RNA and to a smaller extent in the double stranded DNA which block DNA replication [13, 22, 23, 102]....
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...At the beginning the RNA modifications were thought to be irreversible, but recent discoveries have shown that at least some of the modifications are reversible [13]....
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TL;DR: It is shown that this approach can reprogram multiple human cell types to pluripotency with efficiencies that greatly surpass established protocols and represents a safe, efficient strategy for somatic cell reprogramming and directing cell fate that has broad applicability for basic research, disease modeling, and regenerative medicine.
2,627 citations
"Dysregulations of Functional RNA Mo..." refers methods in this paper
...With the transfection of m5C- and pseudouridine-modified synthetic mRNAs encoding the four pluripotency factors (Yamanaka factors) KLF4, c-MYC, OCT4, and SOX2, Warren and colleagues were able to reprogram the differentiated human cells to pluripotent cells [167]....
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TL;DR: In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereasYTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m( 6)A.
2,179 citations
"Dysregulations of Functional RNA Mo..." refers background in this paper
...Depending on the modifying enzyme and its subcellular localization as well as the modification reader, the modification causes changes in the translational efficiency of the transcripts, regulates their shuttling between cytoplasm and nucleus, determines their stability or recruits splicing factors thereby determining splice variants [184-188]....
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