Modulation of circRNA Metabolism by m6A Modification

Timoteo, Gaia Di; Dattilo, Dario; Centrón-Broco, Alvaro; Colantoni, Alessio; Guarnacci, Marco; Rossi, Francesca Maria; Incarnato, Danny; Oliviero, Salvatore; Fatica, Alessandro; Morlando, Mariangela; Bozzoni, Irene

doi:10.1016/j.celrep.2020.107641

Cited by 230 publications

(180 citation statements)

References 43 publications

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“…As a primary component of the m6A methyltransferase complex, KIAA1429 has recently been demonstrated to promote HCC progression [11,12]. More importantly, growing evidence suggested that the biogenesis and function of circRNAs could be regulated by m6A modi cation and m6A regulated-circRNAs may provide potential therapeutic targets [17,18]. In our present work, we identi ed circDLC1 as a novel KIAA1429-regulated circRNA, which was clinically relevant to favorable prognosis of HCC patients.…”

Section: Discussionmentioning

confidence: 61%

“…The main function of circRNAs in tumor is sponging microRNAs (miRNAs), encoding protein or binding protein (14)(15)(16). Interestingly, more recent studies revealed that methyltransferase-like-3 (METTL3), core complex of methyltransferase, is involved in circRNA biogenesis and function by regulating m6A modi cation (17,18). Thus, the speci c roles of KIAA1429 in mediating circRNAs pathway are urgently needed to explore.…”

Section: Introductionmentioning

confidence: 99%

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Circular RNA circDLC1 Inhibits MMP1-Mediated Liver Cancer Progression via Interaction with HuR

Liu

Lan

et al. 2020

Preprint

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Background: N6-methyladenosine (m6A) modification has been demonstrated to be closely related to cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. However, the involvement of circular RNAs (circRNAs) in KIAA1429-mediated HCC progression is still unknown.Methods: RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (m6A-seq) were utilized to identify KIAA1429-regulated circRNAs. The effects of circDLC1 on proliferation and metastasis of hepatoma cells were examined in vitro and in vivo. RT-qPCR was used to measure the expression of circDLC1 in HCC tissues and hepatoma cells. RNA FISH, RIP assays and biotin-labeled RNA pull-down were used to investigate the downstream effector of circDLC1. The downstream targets of circDLC1 were identified using RNA-seq.Results: Our data demonstrated that circDLC1 was downregulated in HCC tissues and closely relevant to favorable prognosis. Overexpression of circDLC1 inhibited the proliferation and motility of hepatoma cells in vitro and in vivo, while silencing of circDLC1 played the opposite role. Mechanistic investigations revealed that circDLC1 could bind to RNA-binding protein HuR, which subsequently reduced the interaction between HuR and MMP1 mRNAs, thus inhibited the expression of MMP1, finally contributed to inhibition of HCC progression.Conclusion: Our work suggests that circDLC1, a downstream target of KIAA1429, is a promising prognostic marker for HCC patients, and the circDLC1-HuR-MMP1 axis may serve as a potential therapeutic target for HCC treatment.

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Section: Discussionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Circular RNA circDLC1 Inhibits MMP1-Mediated Liver Cancer Progression via Interaction with HuR

Liu

Lan

et al. 2020

Preprint

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“…Di et al confirmed that some circRNA-specific m 6 A loci may be related to the production of circRNAs. The authors found that circZNF609 contains a circRNA-specific m 6 A locus and that when the specific site is mutated, the production of circZNF609 is significantly inhibited [ 41 ]. In addition, base pairing between Alu elements and dimerization of RBPs in introns play essential regulatory roles in the formation of circRNAs alternative splicing [ 33 , 42 ].…”

Section: Biogenesis and Characteristics Of Circrnasmentioning

confidence: 99%

CircRNAs: biogenesis, functions, and role in drug-resistant Tumours

Kong

et al. 2020

Mol Cancer

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Targeted treatment, which can specifically kill tumour cells without affecting normal cells, is a new approach for tumour therapy. However, tumour cells tend to acquire resistance to targeted drugs during treatment. Circular RNAs (circRNAs) are single-stranded RNA molecules with unique structures and important functions. With the development of RNA sequencing technology, circRNAs have been found to be widespread in tumour-resistant cells and to play important regulatory roles. In this review, we present the latest advances in circRNA research and summarize the various mechanisms underlying their regulation. Moreover, we review the role of circRNAs in the chemotherapeutic resistance of tumours and explore the clinical value of circRNA regulation in treating tumour resistance.

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“…Among these, YTH N 6methyladenosine RNA-binding protein 1 (YTHDF1) and YTH domain-containig 2 (YTHDC2) predominantly promote translational efficiency, while YTHDF2 accelerates mRNA decay by trafficking target mRNAs to P bodies for degradation [9,10,25]. YTHDF3 facilitates the functions of both YTHDF1 and 2 and also enables translation of circular RNAs (circRNAs) [26][27][28][29]. YTHDC1 participates in RNA splicing, circRNA synthesis, Xist-mediated X chromosome inactivation, and global regulation of chromatin accessibility [11,20,29,30].…”

Section: Overview Of the M 6 A Machinerymentioning

confidence: 99%

“…YTHDF3 facilitates the functions of both YTHDF1 and 2 and also enables translation of circular RNAs (circRNAs) [26][27][28][29]. YTHDC1 participates in RNA splicing, circRNA synthesis, Xist-mediated X chromosome inactivation, and global regulation of chromatin accessibility [11,20,29,30]. Additional readers include eukaryotic initiation factor 3 (eIF3), insulin-like growth factor 2-binding protein (IGF2BP) family proteins, and heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins hnRNPA2B1, hnRNPC, and hnRNPG [12,[31][32][33][34][35].…”

Section: Overview Of the M 6 A Machinerymentioning

confidence: 99%

The Role of RNA Epigenetic Modification in Normal and Malignant Hematopoiesis

et al. 2020

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Purpose of Review RNA epigenetic modifications have been identified as novel, dynamic regulators of gene expression, with important impacts on stem cell fate decisions. Here, we examine the functions of RNA modifications, with a focus on N 6methyladenosine (m 6 A), in hematopoietic stem cells under normal conditions and in malignancy. Recent Findings The m 6 A RNA modification is a critical regulator of hematopoiesis. Disruption of different elements of the m 6 A machinery can skew the balance of self-renewal and differentiation in normal hematopoietic stem cells. The m 6 A reader, writer, and eraser proteins are also overexpressed in myeloid leukemia, and disruption of their function impairs leukemogenesis. RNA m 6 A modification governs important aspects of immune system function, including immune cell development, immune signaling, and recognition of RNA as foreign or self. In hematopoietic stem cells, endogenously derived double-stranded RNA can form in the absence of m 6 A, inducing deleterious inflammatory pathways which compromise stem cell function. Summary The RNA modification m 6 A exerts a variety of functions in normal hematopoietic stem cells as well as leukemic cells. Pharmacologic modulation of different elements of the m 6 A machinery provides a promising avenue for ex vivo expansion of hematopoietic stem cells in the transplant setting, as well as for leukemia therapy. Keywords RNA modification. N 6-methyladenosine. m 6 A. Hematopoiesis. dsRNA This article is part of the Topical Collection on Classical Signalling Pathways * Radovan Vasic

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Modulation of circRNA Metabolism by m6A Modification

Cited by 230 publications

References 43 publications

Circular RNA circDLC1 Inhibits MMP1-Mediated Liver Cancer Progression via Interaction with HuR

Circular RNA circDLC1 Inhibits MMP1-Mediated Liver Cancer Progression via Interaction with HuR

CircRNAs: biogenesis, functions, and role in drug-resistant Tumours

The Role of RNA Epigenetic Modification in Normal and Malignant Hematopoiesis

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