Methylation Modification, Alternative Splicing, and Noncoding RNA Play a Role in Cancer Metastasis through Epigenetic Regulation

Metastasis is the leading cause of cancer-related deaths. Understanding the pathogenesis of metastasis at the molecular levels is of great significance for cancer research. However, the molecular diagnosis or treatment of cancer metastasis is limited. Accumulating and growing evidence shows that epigenetic changes are present in all human cancers, and epigenetic regulation is an indispensable factor to promote tumor metastasis. With the deepening of research and the advancement of technology, the function and mechanism of epigenetic regulation, including DNA methylation, histone/RNA modification, and precursor messenger RNA alternative splicing and noncoding RNAs, has become more increasingly clear. At present, the application of epigenetic therapies in tumor treatment is becoming a feasible therapeutic route. In this review, we looked for the key molecules in epigenetic regulation and discuss their relative regulating mechanisms in cancer metastasis. Furthermore, we highlight promising therapeutic strategies, including monitoring serum DNA for diagnostic purposes and early phase clinical trial therapies that target DNA and histone methylation. This may also be beneficial in finding new targets for further prognosis and diagnosis of cancer metastasis.

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Multiple Functions of RNA Methylation in T Cells: A Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.627455 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yinong Chao ◽

Hua-Bing Li ◽

Jing Zhou

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Messenger Rna ◽

Noncoding Rna ◽

Epigenetic Modification ◽

Biological Activities ◽

Biological Significance ◽

Rna Modification ◽

Rna Methylation

RNA modification represents one of the most ubiquitous mechanisms of epigenetic regulation and plays an essential role in modulating cell proliferation, differentiation, fate determination, and other biological activities. At present, over 170 types of RNA modification have been discovered in messenger RNA (mRNA) and noncoding RNA (ncRNA). RNA methylation, as an abundant and widely studied epigenetic modification, is crucial for regulating various physiological or pathological states, especially immune responses. Considering the biological significance of T cells as a defense against viral infection and tumor challenge, in this review, we will summarize recent findings of how RNA methylation regulates T cell homeostasis and function, discuss the open questions in this rapidly expanding field of RNA modification, and provide the theoretical basis and potential therapeutic strategies involving targeting of RNA methylation to orchestrate beneficial T cell immune responses.

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Computational Evidence of NAGNAG Alternative Splicing in Human Large Intergenic Noncoding RNA

BioMed Research International ◽

10.1155/2014/736798 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Xiaoyong Sun ◽

Simon M. Lin ◽

Xiaoyan Yan

Keyword(s):

Alternative Splicing ◽

Messenger Rna ◽

Noncoding Rna ◽

Data Sets ◽

Posttranslational Regulation ◽

Biological Processes ◽

Rna Seq ◽

Splice Site Selection ◽

Protein Coding ◽

Sequencing Studies

NAGNAG alternative splicing plays an essential role in biological processes and represents a highly adaptable system for posttranslational regulation of gene function. NAGNAG alternative splicing impacts a myriad of biological processes. Previous studies of NAGNAG largely focused on messenger RNA. To the best of our knowledge, this is the first study testing the hypothesis that NAGNAG alternative splicing is also operative in large intergenic noncoding RNA (lincRNA). The RNA-seq data sets from recent deep sequencing studies were queried to test our hypothesis. NAGNAG alternative splicing of human lincRNA was identified while querying two independent RNA-seq data sets. Within these datasets, 31 NAGNAG alternative splicing sites were identified in lincRNA. Notably, most exons of lincRNA containing NAGNAG acceptors were longer than those from protein-coding genes. Furthermore, presence of CAG coding appeared to participate in the splice site selection. Finally, expression of the isoforms of NAGNAG lincRNA exhibited tissue specificity. Together, this study improves our understanding of the NAGNAG alternative splicing in lincRNA.

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Natural Antisense Transcript PEBP1P3 Regulates the RNA Expression, DNA Methylation and Histone Modification of CD45 Gene

Genes ◽

10.3390/genes12050759 ◽

2021 ◽

Vol 12 (5) ◽

pp. 759

Author(s):

Zhongjing Su ◽

Guangyu Liu ◽

Bin Zhang ◽

Ze Lin ◽

Dongyang Huang

Keyword(s):

Dna Methylation ◽

Alternative Splicing ◽

Histone Modification ◽

Antisense Rna ◽

Noncoding Rna ◽

Antisense Transcript ◽

Natural Antisense Transcript ◽

Regulation Of Expression ◽

Splicing Isoforms ◽

Intron 2

The leukocyte common antigen CD45 is a transmembrane phosphatase expressed on all nucleated hemopoietic cells, and the expression levels of its splicing isoforms are closely related to the development and function of lymphocytes. PEBP1P3 is a natural antisense transcript from the opposite strand of CD45 intron 2 and is predicted to be a noncoding RNA. The genotype-tissue expression and quantitative PCR data suggested that PEBP1P3 might be involved in the regulation of expression of CD45 splicing isoforms. To explore the regulatory mechanism of PEBP1P3 in CD45 expression, DNA methylation and histone modification were detected by bisulfate sequencing PCR and chromatin immunoprecipitation assays, respectively. The results showed that after the antisense RNA PEBP1P3 was knocked down by RNA interference, the DNA methylation of CD45 intron 2 was decreased and histone H3K9 and H3K36 trimethylation at the alternative splicing exons of CD45 DNA was increased. Knockdown of PEBP1P3 also increased the binding levels of chromatin conformation organizer CTCF at intron 2 and the alternative splicing exons of CD45. The present results indicate that the natural antisense RNA PEBP1P3 regulated the alternative splicing of CD45 RNA, and that might be correlated with the regulation of histone modification and DNA methylation.

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The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

Molecular Cancer ◽

10.1186/s12943-021-01356-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mohammad Burhan Uddin ◽

Zhishan Wang ◽

Chengfeng Yang

Keyword(s):

Signaling Pathways ◽

Malignant Transformation ◽

Noncoding Rna ◽

Rna Modification ◽

Oncogenic Signaling ◽

Aberrant Expression ◽

Rna Methylation ◽

Rna Molecules ◽

M6a Rna Methylation ◽

Oncogenic Signaling Pathways

AbstractThe 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.

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LncRNA CRNDE attenuates chemoresistance in gastric cancer via SRSF6-regulated alternative splicing of PICALM

Molecular Cancer ◽

10.1186/s12943-020-01299-y ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Feifei Zhang ◽

Hui Wang ◽

Jiang Yu ◽

Xueqing Yao ◽

Shibin Yang ◽

...

Keyword(s):

Gastric Cancer ◽

Alternative Splicing ◽

Noncoding Rna ◽

De Novo ◽

Acquired Resistance ◽

Genetic Alterations ◽

Clinical Samples ◽

Autophagy Flux ◽

Resistance To Chemotherapy

AbstractDe novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC.

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Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration ◽

10.1186/s40035-021-00240-7 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Dunhui Li ◽

Craig Stewart McIntosh ◽

Frank Louis Mastaglia ◽

Steve Donald Wilton ◽

May Thandar Aung-Htut

Keyword(s):

Alternative Splicing ◽

Neurodegenerative Diseases ◽

Messenger Rna ◽

Muscular Atrophy ◽

Single Gene ◽

Synaptic Function ◽

Coding Regions ◽

Splicing Defects ◽

The Impact ◽

Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

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Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival

Journal of Oncology ◽

10.1155/2020/8681361 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuyun Wu ◽

Ningbo Hao ◽

Suming Wang ◽

Xin Yang ◽

Yufeng Xiao ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Noncoding Rna ◽

Tumor Metastasis ◽

Cancer Metastasis ◽

Survival Rates ◽

Migration And Invasion ◽

Poor Overall Survival ◽

Low Expression ◽

Overall Survival Rates

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.

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