Emerging roles of RNA methylation in gastrointestinal cancers

AbstractRNA methylation has emerged as a fundamental process in epigenetic regulation. Accumulating evidences indicate that RNA methylation is essential for many biological functions, and its dysregulation is associated with human cancer progression, particularly in gastrointestinal cancers. RNA methylation has a variety of biological properties, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C) and 7-methyl guanosine (m7G). Dynamic and reversible methylation on RNA is mediated by RNA modifying proteins called “writers” (methyltransferases) and “erasers” (demethylases). “Readers” (modified RNA binding proteins) recognize and bind to RNA methylation sites, which influence the splicing, stability or translation of modified RNAs. Herein, we summarize the biological functions and mechanisms of these well-known RNA methylations, especially focusing on the roles of m6A in gastrointestinal cancer development.

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Current insights into the implications of m6A RNA methylation and autophagy interaction in human diseases

Cell & Bioscience ◽

10.1186/s13578-021-00661-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xuechai Chen ◽

Jianan Wang ◽

Muhammad Tahir ◽

Fangfang Zhang ◽

Yuanyuan Ran ◽

...

Keyword(s):

Intervertebral Disc Degeneration ◽

Rna Binding ◽

Rna Binding Proteins ◽

Degradation Process ◽

Human Diseases ◽

Rna Modification ◽

Rna Methylation ◽

M6a Rna Methylation ◽

The Impact

AbstractAutophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.

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The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00450-x ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xiulin Jiang ◽

Baiyang Liu ◽

Zhi Nie ◽

Lincan Duan ◽

Qiuxia Xiong ◽

...

Keyword(s):

Cancer Progression ◽

Molecular Mechanisms ◽

Target Genes ◽

Rna Modification ◽

Biological Functions ◽

Rna Methylation ◽

Downstream Target ◽

Different Types ◽

M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

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Lin28, a major translation reprogramming factor, gains access to YB-1-packaged mRNA through its cold-shock domain

Communications Biology ◽

10.1038/s42003-021-01862-3 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Anastasiia Samsonova ◽

Krystel El Hage ◽

Bénédicte Desforges ◽

Vandana Joshi ◽

Marie-Jeanne Clément ◽

...

Keyword(s):

Cancer Progression ◽

Cold Shock ◽

Rna Binding ◽

Rna Binding Proteins ◽

Rna Binding Protein ◽

Large Set ◽

Core Component ◽

The Core ◽

Cold Shock Domain ◽

Global Translation

AbstractThe RNA-binding protein Lin28 (Lin28a) is an important pluripotency factor that reprograms translation and promotes cancer progression. Although Lin28 blocks let-7 microRNA maturation, Lin28 also binds to a large set of cytoplasmic mRNAs directly. However, how Lin28 regulates the processing of many mRNAs to reprogram global translation remains unknown. We show here, using a structural and cellular approach, a mixing of Lin28 with YB-1 (YBX1) in the presence of mRNA owing to their cold-shock domain, a conserved β-barrel structure that binds to ssRNA cooperatively. In contrast, the other RNA binding-proteins without cold-shock domains tested, HuR, G3BP-1, FUS and LARP-6, did not mix with YB-1. Given that YB-1 is the core component of dormant mRNPs, a model in which Lin28 gains access to mRNPs through its co-association with YB-1 to mRNA may provide a means for Lin28 to reprogram translation. We anticipate that the translational plasticity provided by mRNPs may contribute to Lin28 functions in development and adaptation of cancer cells to an adverse environment.

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The Emerging Roles of the RNA Binding Protein QKI in Cardiovascular Development and Function

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.668659 ◽

2021 ◽

Vol 9 ◽

Author(s):

Xinyun Chen ◽

Jianwen Yin ◽

Dayan Cao ◽

Deyong Xiao ◽

Zhongjun Zhou ◽

...

Keyword(s):

Cancer Progression ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Property ◽

Cardiovascular Development ◽

Potential Link ◽

Alternatively Spliced ◽

Unique Cell ◽

Carboxy Terminal ◽

And Function

RNA binding proteins (RBPs) have a broad biological and physiological function and are critical in regulating pre-mRNA posttranscriptional processing, intracellular migration, and mRNA stability. QKI, also known as Quaking, is a member of the signal transduction and activation of RNA (STAR) family, which also belongs to the heterogeneous nuclear ribonucleoprotein K- (hnRNP K-) homology domain protein family. There are three major alternatively spliced isoforms, QKI-5, QKI-6, and QKI-7, differing in carboxy-terminal domains. They share a common RNA binding property, but each isoform can regulate pre-mRNA splicing, transportation or stability differently in a unique cell type-specific manner. Previously, QKI has been known for its important role in contributing to neurological disorders. A series of recent work has further demonstrated that QKI has important roles in much broader biological systems, such as cardiovascular development, monocyte to macrophage differentiation, bone metabolism, and cancer progression. In this mini-review, we will focus on discussing the emerging roles of QKI in regulating cardiac and vascular development and function and its potential link to cardiovascular pathophysiology.

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SAM68: Signal Transduction and RNA Metabolism in Human Cancer

BioMed Research International ◽

10.1155/2015/528954 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 42

Author(s):

Paola Frisone ◽

Davide Pradella ◽

Anna Di Matteo ◽

Elisa Belloni ◽

Claudia Ghigna ◽

...

Keyword(s):

Cell Cycle ◽

Signal Transduction ◽

Nuclear Export ◽

Cell Biology ◽

Rna Binding ◽

Rna Binding Proteins ◽

Splice Variants ◽

Human Cancer ◽

Rna Metabolism ◽

Regulatory Sequences

Alterations in expression and/or activity of splicing factors as well as mutations incis-acting splicing regulatory sequences contribute to cancer phenotypes. Genome-wide studies have revealed more than 15,000 tumor-associated splice variants derived from genes involved in almost every aspect of cancer cell biology, including proliferation, differentiation, cell cycle control, metabolism, apoptosis, motility, invasion, and angiogenesis. In the past decades, several RNA binding proteins (RBPs) have been implicated in tumorigenesis. SAM68 (SRC associated in mitosis of 68 kDa) belongs to the STAR (signal transduction and activation of RNA metabolism) family of RBPs. SAM68 is involved in several steps of mRNA metabolism, from transcription to alternative splicing and then to nuclear export. Moreover, SAM68 participates in signaling pathways associated with cell response to stimuli, cell cycle transitions, and viral infections. Recent evidence has linked this RBP to the onset and progression of different tumors, highlighting misregulation of SAM68-regulated splicing events as a key step in neoplastic transformation and tumor progression. Here we review recent studies on the role of SAM68 in splicing regulation and we discuss its contribution to aberrant pre-mRNA processing in cancer.

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Roles of Splicing Factors in Hormone-Related Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms21051551 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1551 ◽

Cited By ~ 3

Author(s):

Toshihiko Takeiwa ◽

Yuichi Mitobe ◽

Kazuhiro Ikeda ◽

Kuniko Horie-Inoue ◽

Satoshi Inoue

Keyword(s):

Cancer Progression ◽

Rna Binding ◽

Rna Binding Proteins ◽

Mrna Isoforms ◽

Targeting Therapy ◽

Biological Phenomena ◽

New Strategy ◽

Heterogeneous Nuclear Ribonucleoproteins ◽

Prostate Cancers ◽

Mrna Precursor

Splicing of mRNA precursor (pre-mRNA) is a mechanism to generate multiple mRNA isoforms from a single pre-mRNA, and it plays an essential role in a variety of biological phenomena and diseases such as cancers. Previous studies have demonstrated that cancer-specific splicing events are involved in various aspects of cancers such as proliferation, migration and response to hormones, suggesting that splicing-targeting therapy can be promising as a new strategy for cancer treatment. In this review, we focus on the splicing regulation by RNA-binding proteins including Drosophila behavior/human splicing (DBHS) family proteins, serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs) in hormone-related cancers, such as breast and prostate cancers.

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Revisiting 3D chromatin architecture in cancer development and progression

Nucleic Acids Research ◽

10.1093/nar/gkaa747 ◽

2020 ◽

Vol 48 (19) ◽

pp. 10632-10647

Author(s):

Yuliang Feng ◽

Siim Pauklin

Keyword(s):

Phase Separation ◽

Cancer Progression ◽

Genome Organization ◽

State Of The Art ◽

Human Cancer ◽

Cancer Development ◽

Transcriptional Dysregulation ◽

Chromatin Architecture ◽

Novel Approaches ◽

Promoter Interaction

Abstract Cancer development and progression are demarcated by transcriptional dysregulation, which is largely attributed to aberrant chromatin architecture. Recent transformative technologies have enabled researchers to examine the genome organization at an unprecedented dimension and precision. In particular, increasing evidence supports the essential roles of 3D chromatin architecture in transcriptional homeostasis and proposes its alterations as prominent causes of human cancer. In this article, we will discuss the recent findings on enhancers, enhancer–promoter interaction, chromatin topology, phase separation and explore their potential mechanisms in shaping transcriptional dysregulation in cancer progression. In addition, we will propose our views on how to employ state-of-the-art technologies to decode the unanswered questions in this field. Overall, this article motivates the study of 3D chromatin architecture in cancer, which allows for a better understanding of its pathogenesis and develop novel approaches for diagnosis and treatment of cancer.

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Control of Cytokine mRNA Expression by RNA-binding Proteins and microRNAs

Journal of Dental Research ◽

10.1177/0022034512437372 ◽

2012 ◽

Vol 91 (7) ◽

pp. 651-658 ◽

Cited By ~ 60

Author(s):

V. Palanisamy ◽

A. Jakymiw ◽

E.A. Van Tubergen ◽

N.J. D’Silva ◽

K.L. Kirkwood

Keyword(s):

Cancer Progression ◽

Mrna Stability ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Periodontal Diseases ◽

Pharyngeal Cancer ◽

Cytokine Mrna ◽

Mediators Of Inflammation ◽

The Stability

Cytokines are critical mediators of inflammation and host defenses. Regulation of cytokines can occur at various stages of gene expression, including transcription, mRNA export, and post- transcriptional and translational levels. Among these modes of regulation, post-transcriptional regulation has been shown to play a vital role in controlling the expression of cytokines by modulating mRNA stability. The stability of cytokine mRNAs, including TNFα, IL-6, and IL-8, has been reported to be altered by the presence of AU-rich elements (AREs) located in the 3′-untranslated regions (3′UTRs) of the mRNAs. Numerous RNA-binding proteins and microRNAs bind to these 3′UTRs to regulate the stability and/or translation of the mRNAs. Thus, this paper describes the cooperative function between RNA-binding proteins and miRNAs and how they regulate AU-rich elements containing cytokine mRNA stability/degradation and translation. These mRNA control mechanisms can potentially influence inflammation as it relates to oral biology, including periodontal diseases and oral pharyngeal cancer progression.

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The Regulatory Functions of Circular RNAs in Digestive System Cancers

Cancers ◽

10.3390/cancers12030770 ◽

2020 ◽

Vol 12 (3) ◽

pp. 770 ◽

Cited By ~ 4

Author(s):

Xiao Yuan ◽

Ya Yuan ◽

Zhi He ◽

Diyan Li ◽

Bo Zeng ◽

...

Keyword(s):

Digestive System ◽

Rna Binding ◽

Rna Binding Proteins ◽

Circular Rna ◽

Research Progress ◽

Circular Rnas ◽

Biological Functions ◽

Ribonucleic Acids ◽

Mirna Sponges ◽

And Biological Markers

Circular ribonucleic acids (circRNAs), which are a type of covalently closed circular RNA, are receiving increasing attention. An increasing amount of evidence suggests that circRNAs are involved in the biogenesis and development of multiple diseases such as digestive system cancers. Dysregulated circRNAs have been found to act as oncogenes or tumour suppressors in digestive system cancers. Moreover, circRNAs are related to ageing and a wide variety of processes in tumour cells, such as cell apoptosis, invasion, migration, and proliferation. Moreover, circRNAs can perform a remarkable multitude of biological functions, such as regulating splicing or transcription, binding RNA-binding proteins to enable function, acting as microRNA (miRNA) sponges, and undergoing translated into proteins. However, in digestive system cancers, circRNAs function mainly as miRNA sponges. Herein, we summarise the latest research progress on biological functions of circRNAs in digestive system cancers. This review serves as a synopsis of potential therapeutic targets and biological markers for digestive system cancer.

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