Emerging Epigenetic Regulation of Circular RNAs in Human Cancer

Molecular Therapy — Nucleic Acids, Journal Year: 2019, Volume and Issue: 16, P. 589 - 596

Published: April 19, 2019

Circular RNAs (circRNAs) are novel members of the noncoding RNA family. Their characteristic covalent closed-loop structure endows circRNAs that much more stable than corresponding linear transcript. ubiquitous in eukaryotic cells, and their functions diverse include adsorbing microRNAs (miRNAs; acting as miRNA sponges), regulating transcription, interacting with RNA-binding proteins, translating deriving pseudogenes. Moreover, associated occurrence progression a variety cancers, new biomarkers for early diagnosis to evaluate curative effects patient prognosis. Here, this paper briefly describes characteristics circRNAs, it further concludes relationship between human cancer. Based on potential encoded family can be divided into two categories, coding RNAs; long RNA, riRNA, tRNA, nsRNA, microRNA (miRNA). In recent years, research has made great progress identification RNAs, which involved biological processes.1Wilusz J.E. Sharp P.A. Molecular biology. A circuitous route RNA.Science. 2013; 340: 440-441Crossref PubMed Scopus (384) Google Scholar, 2Zhao W. Ma X. Liu L. Chen Q. Z. Zhang S. Wang Li H. Wu J. SNHG20: vital lncRNA multiple cancers.J. Cell. Physiol. 2019; (Published online January 15, 2019)https://doi.org/10.1002/jcp.28143Crossref (47) Scholar have nearly 30 years history. They special class derived from back-splicing or exon skipping pre-mRNAs. Unlike do not 5-cap 3-poly(A) tails, produced by exons, downstream 3-splicing donor is connected reverse bond upstream 5-split acceptor.3Pieler T. Theunissen O. TFIIIA: nine fingers--three hands?.Trends Biochem. Sci. 1993; 18: 226-230Abstract Full Text PDF (39) due circular structure, they easily degraded exonucleases, thus having longer half-life. considered inert by-products abnormally spliced RNAs. With emergence high-throughput sequencing, an increasing number been found cells. Increasing evidence shows expression profiles carcinoid tissues different those normal tissues.4Shi P. Sun He B. Song Kong Xue Profiles differentially expressed esophageal breast cancer.Cancer Manag. Res. 2018; 10: 2207-2221Crossref (35) 5Cheng X.Y. Shen [Circular Lung Cancer Research: Biogenesis, Functions Roles].Zhongguo Fei Ai Za Zhi. 21: 50-56PubMed addition, reported participate cellular cancer-related physiological processes, including cancer initiation, progression, metastasis.6Qu Yang Gao Y. Shang R. Dou K. RNA: star RNAs.Cancer Lett. 2015; 365: 141-148Crossref (1222) Therefore, in-depth analysis should help clarify epigenetic level mechanisms. According differences genome constituent sequences, three categories: exon-derived intron-derived composed exons introns.7Ashwal-Fluss Meyer M. Pamudurti N.R. Ivanov A. Bartok Hanan Evantal N. Memczak Rajewsky Kadener circRNA biogenesis competes pre-mRNA splicing.Mol. 2014; 56: 55-66Abstract (1951) 8Kelly Greenman C. Cook P.R. Papantonis Exon Skipping Is Correlated Circularization.J. Mol. Biol. 427: 2414-2417Crossref (245) 9Chen I. C.Y. Chuang T.J. identification, function exonic RNAs.Wiley Interdiscip. Rev. RNA. 6: 563-579Crossref (281) Three models used illuminate possible formation circRNAs: lariat-driven circularization, intron pairing-driven protein-driven circularization (Figure 1). During (cassette-on), lariat still reserves skipped exon(s). circle when splicing occurs before decomposed debranching enzymes. Lariat-driven also known exon-skipping mechanism. The partially folds during causing 5′ site (donor site) approach attack 3′ (receptor intron, whereby formed folded region, while remaining form mRNA.10Jeck W.R. Sorrentino J.A. Slevin M.K. Burd C.E. Marzluff W.F. Sharpless N.E. abundant, conserved, ALU repeats.RNA. 19: 141-157Crossref (2826) 11Wilusz 360° view RNAs: From functions.Wiley 9: e1478Crossref (300) This mechanism most circRNAs. For example, Kelly et al.8Kelly umbilical vein endothelial cells stimulated tumor necrosis factor α growth β contained large circularization. Intron direct Reverse complementary sequences flanks introns mediate Flanking (especially Alu sequences) play crucial part perfectly matched promote circRNAs.12Rybak-Wolf Stottmeister Glažar Jens Pino Giusti Behm Ashwal-Fluss al.Circular Mammalian Brain Are Highly Abundant, Conserved, Dynamically Expressed.Mol. 58: 870-885Abstract (1484) 13Koh Pan Gawad Fan H.C. Kerchner G.A. Wyss-Coray Blumenfeld Y.J. El-Sayed Y.Y. Quake S.R. Noninvasive vivo monitoring tissue-specific global gene humans.Proc. Natl. Acad. USA. 111: 7361-7366Crossref (200) procedure, patterns according whether partial retained, namely, (EcircRNAs) coexist (EIciRNAs).14Bahn J.H. F. Chan T.M. Lin Kim Wong D.T. Xiao landscape microRNA, Piwi-interacting saliva.Clin. Chem. 61: 221-230Crossref (489) Hsa-circ-POLR2A typical circRNA.13Koh proteins (RBPs) shorten distance receptor binding flanks, promoting exons. Muscleblind protein quaking RBPs circMbl circQKI, respectively.15Lasda E. Parker diversity function.RNA. 20: 1829-1842Crossref (848) 16Ivanov Wyler Torti Porath H.T. Orejuela M.R. Piechotta Levanon E.Y. Landthaler Dieterich Analysis reveals hallmarks animals.Cell Rep. 170-177Abstract (673) role some There hypotheses first hypothesis crosses enzyme then cleaves at both ends crossed exon, (lariat);7Ashwal-Fluss therefore, generated splicing. single Another that, base-paired, exon's end tail head, spliceosome bound receptor, resulting introns, cyclized released circRNA.8Kelly Many EcircRNAs contain encode normally standard sites through copolymer Genome-wide sequencing (RNA-seq) data suggests abundant mammalian transcriptome, EcircRNA conserved evolutionary variation, revealing functions.10Jeck 12Rybak-Wolf 17Wilusz Unexpected outputs many protein-coding genes.RNA 2017; 14: 1007-1017Crossref (79) Specifically, indicated steady plasma13Koh saliva,14Bahn suggesting may diagnostic biomarkers. contrast EcircRNAs, (IciRNAs) 3′∼5′ head-to-tail junction regions differ stability, subcellular localization, abundance, preservation, function. IciRNAs circularized chain branchpoints 2′∼5′, degenerating branchpoint avoiding detachment degradation specific way; actually stabilized lariats.15Lasda synthesis requires important site: c-rich containing 11 nt near terminus, length 7 nt, base-rich GU RNA-splicing branch site.16Ivanov Approximately 20% EIciRNAs retain retention would make subclass unique retaining IciRNAs. Mainly located nucleus, interact U1 small nuclear ribonucleoprotein particle (snRNP) transcription parental genes. regulation expression, enhance genes cis emphasize transcriptional strategy RNA-RNA interaction (snRNA).17Wilusz 18Li Huang Bao Zhong G. Yu Hu Dai al.Exon-intron regulate nucleus.Nat. Struct. 22: 256-264Crossref (1852) closed highly resistant digestion; preliminarily purified identified following molecular biology methods.19Jeck Detecting characterizing RNAs.Nat. Biotechnol. 32: 453-461Crossref (1745) (1) Most exonuclease R, niacin phosphatase 5′-terminal exonuclease, retained. Then, circRNA-specific primers quantitative samples, determine quantify after treatment.19Jeck 20Suzuki Zuo M.Q. Malhotra Mayeda Characterization RNase R-digested source consists splicing.Nucleic Acids 2006; 34: e63Crossref (428) (2) no polar end, migration rate cross-linked gel slower Compared homologous nucleic acids fewer weakly gels slower. northern blot analysis.21Tabak H.F. Van der Horst Smit Winter A.J. Mul Groot Koerkamp M.J. Discrimination circles, interlocked circles lariats using two-dimensional polyacrylamide electrophoresis.Nucleic 1988; 16: 6597-6605Crossref (33) 22Suzuki Tsukahara R RNAs.Int. 15: 9331-9342Crossref (314) (3) Fluorescence situ hybridization localize level, interfering (siRNAs) antisense oligonucleotides interfere verify circRNAs.23Li al.Corrigendum: Exon-intron 24: 194Crossref (60) 24Zhang X.O. Xiang J.F. Yin Q.F. Xing Y.H. Zhu L.L. intronic RNAs.Mol. 51: 792-806Abstract (1529) traditional methods, combination bioinformatics provides shortcut discovery low abundance. back-splicing, RNA-seq algorithm extremely inefficient distinguishing structures. Researchers effectively improved strategies algorithms follows: assuming forms rearrangement, candidate sequence boundary was constructed compared data;25Salzman R.E. Olsen M.N. P.L. Brown P.O. Cell-type features expression.PLoS Genet. e1003777Crossref (1391) directly alignment algorithms; detected cDNA designing splice sequences.26Hoffmann Otto Doose Tanzer Langenberger D. Christ Kunz Holdt L.M. Teupser Hackermüller Stadler P.F. multi-split mapping splicing, trans-splicing fusion detection.Genome R34Crossref (180) At present, map-splice,27Li Diao Long non-coding HOXD-AS1 cancer.Clin. Chim. Acta. 487: 197-201Crossref (36) Circ Seq,10Jeck CIRI,28Gao Zhao CIRI: efficient unbiased de novo identification.Genome 4Crossref (670) explorer.29Zhang H.B. Lu Complementary sequence-mediated circularization.Cell. 159: 134-147Abstract CIRI annotation-related only detect transcribed intergenomic but applied annotated unannotated eukaryotes. Since lack poly(A) common oligomeric dT enrichment method ineffective. Ribo-Zero kit, eliminate rRNA remove enrich circRNAs.20Suzuki miRNAs sponges, selective RBPs, pseudogenes, transporting substances information. presented Figure 2. response element (MRE) binds prevents them target mRNAs.30Memczak Elefsinioti Krueger Rybak Maier Mackowiak S.D. Gregersen L.H. Munschauer animal regulatory potency.Nature. 495: 333-338Crossref (5161) 31Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen Damgaard C.K. Kjems Natural sponges.Nature. 384-388Crossref (5173) proof sponges cerebellar degeneration-related 1 (CDR1as) determined related its functions. CDR1as reduce brain volume hinder development fetal process zebrafish embryos, injection miR-7 restore development, indicating bind miR-7.31Hansen circHIPK3 2 HIPK3 silenced mRNA significantly inhibited Through luciferase screening, 9 18 specifically miR-124 inhibit activity. However, showed miRNA-binding necessarily strong spongy effect, other confirmed viewpoint.32Guo J.U. Agarwal V. Guo Bartel D.P. Expanded characterization RNAs.Genome 409Crossref (1134) 33You Vlatkovic Babic Will Epstein Tushev Akbalik Glock Quedenau al.Neural synaptic regulated plasticity.Nat. Neurosci. 603-610Crossref (743) act phenomenon remains explained. variable transcription. Variable pre-mRNAs isomers methods (different selected), circMBL, second MBL (muscleblind), pre-mRNA. side MBL-binding sites, strongly MBL. obviously influences cyclization circMbl, based flanks.6Qu 7Ashwal-Fluss translation initiation potentially compete host splices. mode balance levels mRNAs. production posttranscriptional level. c-sirt7 pol complex, leading decreased anchor repeat domain-52 deacetylase-7. EIciRNAs, mostly localized ribosome snRNP genes.18Li like perform functions.34Yin Y.W. Carmichael G.G. snoRNA ends.Mol. 2012; 48: 219-230Abstract (306) 35Li Fox A.H. SPArking Interest Noncoding World: New Class SnoRNA-Stabilized LncRNA Influences Alternative Splicing.Mol. 2016; 64: 435-437Abstract (6) When combined complexes, store them,7Ashwal-Fluss complexes. stably molecules As scaffold DNA provide platform DNA. action Ago2 hydrolysis.36Hansen Wiklund E.D. Villadsen S.B. Statham A.L. Clark S.J. miRNA-dependent silencing involving Ago2-mediated cleavage RNA.EMBO 2011; 30: 4414-4422Crossref (702) Du al.37Du W.W. Dhaliwal B.B. Foxo3 retards cell cycle via forming ternary complexes p21 CDK2.Nucleic 44: 2846-2858Crossref (1079) circ-foxo3 cyclin-dependent kinase (CDK2) inhibitor p21. Abdelmohsen al.38Abdelmohsen Panda A.C. Munk Grammatikakis Dudekula D.B. De Noh K.M. Martindale J.L. Gorospe Identification HuR uncovers suppression PABPN1 CircPABPN1.RNA 361-369Crossref (508) circ-PABPN1 could competitively RBP poly(A)-binding (PABPN1) mRNA, reducing mRNA. plays major cancer, proliferation one main By studying better understood, clues provided study tumorigenesis. species basically proteins. if internal entry point (IRES) inserted start codon functionally transcripts. previously shown vitro, engineered IRES, 40S subunit, IRES translation.39Wang Efficient backsplicing produces translatable mRNAs.RNA. 172-179Crossref (460) 40Thomas L.F. Sætrom depleted polymorphisms sites.Bioinformatics. 2243-2246Crossref (148) Similarly, Escherichia coli, open reading frames GFP transfected express GFP.39Wang al.41Du Yong Awan F.M. Identifying Characterizing circRNA-Protein Interaction.Theranostics. 7: 4183-4191Crossref (380) proved time modified m6A; is, methyl group added sixth base molecule, translation. Zhou al.42Zhou Molinie Daneshvar Pondick J.V. Wittenberghe Giallourakis C.C. Mullen Genome-Wide Maps m6A Identify Widespread Cell-Type-Specific Methylation Patterns Distinct mRNAs.Cell 2262-2276Abstract (249) modification specificity. Legnini al.43Legnini Di Timoteo Rossi Morlando Briganti Sthandier Fatica Santini Andronache Wade al.Circ-ZNF609 Can Be Translated Myogenesis.Mol. 66: 22-37.e9Abstract (1313) circ-ZNF609 muscle translate al.44Yang Yan al.Novel Role FBXW7 Repressing Glioma Tumorigenesis.J. Inst. 110: 304-315Crossref (681) circ-FBXW7 inhibits glioma, significance understanding glioma. Studies th

Language: Английский

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<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

OncoTargets and Therapy, Journal Year: 2020, Volume and Issue: Volume 13, P. 2067 - 2092

Published: March 1, 2020

Abstract: Circular RNA (circRNA) is an intriguing class of with covalently closed-loop structure and highly stable conservative. As new members the ncRNAs, function, mechanism, potential diagnostic biomarker, therapeutic target have raised increased attention. Most circRNAs are presented characteristics abundance, stability, conservatism, often exhibiting tissue/developmental-stage-specific manner. Over 30,000 been identified their unique structures to maintain stability more easily than linear RNAs. An numbers dysregulated involved in several biological processes malignance, such as tumorigenesis, growth, invasion, metastasis, apoptosis, vascularization. Emerging evidence suggests that play important roles by acting miRNA sponge or protein scaffolding, autophagy regulators, interacting RNA-binding (RBP), which may potentially serve a novel promising biomarker for prevention, diagnosis treatment human cancer great significance either scientific research clinic arena. This review introduces concept, major features circRNAs, mainly describes functions clinical relevance well expressions regulatory mechanisms various types cancer, including pathogenesis, mode action, target, signaling pathways, drug resistance, biomarkers. All provide utilities cancer. Keywords: circRNA, sponge, gene splicing transcription,

Language: Английский

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NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma

Oncogene, Journal Year: 2019, Volume and Issue: 39(4), P. 891 - 904

Published: Sept. 30, 2019

Language: Английский

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The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 8

Published: Jan. 25, 2021

Osteoporosis is a metabolic disease characterized by decreased bone mineral density and the destruction of microstructure, which can lead to increased fragility risk fracture. In recent years, with deepening research on pathological mechanism osteoporosis, epigenetics has made significant progress. Epigenetics refers changes in gene expression levels that are not caused sequences, mainly including DNA methylation, histone modification, non-coding RNAs (lncRNA, microRNA, circRNA). play post-transcriptional regulatory role have important functions biological signal network. Studies shown epigenetic mechanisms closely related osteogenic differentiation, osteogenesis, remodeling other metabolism-related processes. Abnormal regulation series diseases, such as osteoporosis. Considering metabolism, we review progress (DNA RNAs) differentiation pathogenesis osteoporosis provide new direction for treatment diseases.

Language: Английский

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Circular RNAs in nucleus pulposus cell function and intervertebral disc degeneration

Cell Proliferation, Journal Year: 2019, Volume and Issue: 52(6)

Published: Oct. 16, 2019

Abstract Intervertebral disc degeneration (IDD) is a common cause of low back pain, which inflicts more global disability than any other condition. Although IDD was deemed to be natural process that comes with ageing, growing body evidence suggested both genetic and environmental factors could modify the development IDD. In this connection, aberrant function nucleus pulposus cells has been implicated in pathogenesis. Circular RNAs are novel class endogenous non‐coding play crucial regulatory roles diverse cellular processes. Recently, deregulation circRNAs found functionally participate development. review, we summarize current knowledge regarding relation their actions on cell functions, including proliferation, apoptosis extracellular matrix synthesis/degradation. The potential clinical utilities as therapeutic targets for management also discussed.

Language: Английский

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Circular RNA HIPK3: A Key Circular RNA in a Variety of Human Cancers

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: May 15, 2020

Circular RNAs (circRNAs), which act as initial factors and promoters in different diseases, are noncoding (ncRNAs) eukaryotes. Accumulating studies have proven that dysregulation of circRNAs is relevant to the occurrence development multiple cancers. circHIPK3, a member circRNA, frequently expressed many such diabetes, age-related cataract, idiopathic pulmonary fibrosis, preeclampsia, osteoblasts retinal vascular dysfunction, leading disease progression. In addition, circHIPK3 also serves an essential role cancer. current studies, circHIPK3-related cancers been identified, including nasopharyngeal carcinoma, gallbladder cancer, lung hepatocellular osteosarcoma, glioma, colorectal ovarian bladder prostate gastric oral squamous cell carcinoma chronic myeloid leukemia. This review demonstrates recent literature on biological functions expounds molecular mechanisms abovementioned malignant tumors.

Language: Английский

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Role of circRNA-miRNA-mRNA interaction network in diabetes and its associated complications

Molecular Therapy — Nucleic Acids, Journal Year: 2021, Volume and Issue: 26, P. 1291 - 1302

Published: Nov. 10, 2021

The majority of the non-protein-coding RNAs are being identified with diversified functions that participate in cellular homeostasis. circular (circRNAs) emerging as noncoding transcripts a key role initiation and development many physiological pathological conditions. advancements high-throughput RNA sequencing bioinformatics tools help us to identify several circRNA regulatory pathways, one which is microRNA (miRNA)-mediated regulation. Besides direct influence over mRNA transcription, can also control target's expression via sponging miRNAs or RNA-binding proteins. Studies have demonstrated dysregulation circRNA-miRNA-mRNA interaction network pathogenesis diseases, including diabetes. This intricate mechanism associated diabetes its complications. review will focus on influences gene progression

Language: Английский

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KGANCDA: predicting circRNA-disease associations based on knowledge graph attention network

Briefings in Bioinformatics, Journal Year: 2021, Volume and Issue: 23(1)

Published: Oct. 27, 2021

Abstract Increasing evidences have proved that circRNA plays a significant role in the development of many diseases. In addition, researches shown can be considered as potential biomarker for clinical diagnosis and treatment disease. Some computational methods been proposed to predict circRNA-disease associations. However, performance these is limited sparsity low-order interaction information. this paper, we propose new method (KGANCDA) associations based on knowledge graph attention network. The graphs are constructed by collecting multiple relationship data among circRNA, disease, miRNA lncRNA. Then, network designed obtain embeddings each entity distinguishing importance information from neighbors. Besides neighbor information, it also capture high-order multisource associations, which alleviates problem sparsity. Finally, multilayer perceptron applied affinity score experiment results show KGANCDA outperforms than other state-of-the-art 5-fold cross validation. Furthermore, case study demonstrates an effective tool

Language: Английский

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Splicing factor derived circular RNA circCAMSAP1 accelerates nasopharyngeal carcinoma tumorigenesis via a SERPINH1/c-Myc positive feedback loop

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Feb. 28, 2022

Abstract Background Circular RNAs play an important role in tumor genesis and progression, but they have not been sufficiently studied patients with nasopharyngeal carcinoma (NPC). Methods The circular RNA, circCAMSAP1, was screened NPC cells by RNA sequencing analysis. expression of circCAMSAP1 tissues examined real-time quantitative polymerase chain reaction (RT-qPCR) situ hybridization. Wound-healing, transwell, MTT flow cytometry assays, nude mouse models were used to explore the effect on proliferation metastasis vitro or vivo. downstream proteins regulated using mass spectrometry. interaction between SERPINH1 mRNA identified immunoprecipitation method luciferase reporter assay. transcription factor c-Myc verified through Co-immunoprecipitation (Co-IP) immunofluorescence. generation RT-qPCR chromatin immunoprecipitation. Finally, splicing factors that promote production explored (RIP). Results We found highly expressed promoted metastasis. Additionally, improved stability binding 3′-untranslated region (3’UTR) . Highly reduced ubiquitination-degradation rate c-Myc, causing increased tumorigenesis. Meanwhile, cooperating 10 (SRSF10), could also CAMSAP1 pre-mRNA back-splicing, forming a positive feedback production, resulting NPC. Conclusions Our findings revealed promotes 3’UTR , suggesting -SERPINH1-c-Myc may serve as prognostic biomarker therapeutic target

Language: Английский

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M6A-modified circRBM33 promotes prostate cancer progression via PDHA1-mediated mitochondrial respiration regulation and presents a potential target for ARSI therapy

International Journal of Biological Sciences, Journal Year: 2023, Volume and Issue: 19(5), P. 1543 - 1563

Published: Jan. 1, 2023

N6-Methyladenosine (m6A) is the most prevalent RNA modification in various types of RNA, including circular RNAs (circRNAs).Mounting evidence has shown that circRNAs may play critical roles diverse malignancies.However, biological relevance m6A prostate cancer (PCa) remains unclear and needs to be elucidated.Our data showed circRBM33 was m6A-modified more highly expressed PCa cells than normal cells/tissues.The vitro vivo experiments downregulation/upregulation inhibited/promoted tumour growth invasion, respectively.Decreasing levels rescued tumour-promoting effect circRBM33.Additionally, once modified by m6A, interacts with FMR1 forming a binary complex sustains mRNA stability PDHA1, downstream target gene.Suppressed/overexpressed lowered/enhanced ATP production, acetyl-CoA NADH/NAD + ratio.Moreover, depletion significantly increased response sensitivity androgen receptor signalling inhibitor (ARSI) therapy, enzalutamide darolutamide, tumours.Our study suggested m6A-mediated circRBM33-FMR1 can activate mitochondrial metabolism stabilizing PDHA1 mRNA, which promotes progression, attenuate ARSI effectiveness treatment.This newly discovered circRNA serve as potential therapeutic for PCa.

Language: Английский

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