The nuclear DICER–circular RNA complex drives the deregulation of the glioblastoma cell microRNAome

Bronisz, Agnieszka; Rooj, Arun K.; Krawczynski, Kamil; Peruzzi, Pierpaolo; Salińska, Elżbieta; Nakano, ﻿Ichiro; Purow, Benjamin; Chiocca, E. Antonio; Godlewski, Jakub

doi:10.1126/sciadv.abc0221

Cited by 40 publications

(32 citation statements)

References 54 publications

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“…Mature miRNAs are thought to operate mostly in the cytosolic compartment; however, in specific conditions some of them could be found in the nucleus (Hwang, Wentzel et al, 2007, Liu, Lei et al, 2018, Politz, Hogan et al, 2009. In agreement with this, in glioma cells, the major enzymatic complex responsible for the final step of miRNA processing, Dicer, is aberrantly localized to the nucleus (Bronisz et al, 2020). To investigate miR-10b subcellular localization, we fractionated glioma cells into cytosolic and nuclear fractions.…”

Section: Mir-10b Binds To Snrna U6 In Glioma Cellsmentioning

confidence: 66%

“…However, miR-10b does not contain such nuclear localization motifs. At least two pieces of evidence provide support for the nuclear miR-10b maturation scenario: first, the finding of Ago2 and, more recently, of Dicer in the nucleus of specific cells, including glioma (Bronisz et al, 2020, Burger, Schlackow et al, 2017, Castanotto, Zhang et al, 2018, Chu, Yokota et al, 2021, Gagnon, Li et al, 2014, Liu et al, 2018, and second, the co-IP of the spliceosomal SART3 and PRPF8 complexes with Ago2, the core endonucleolytic components of RISC that efficiently pools-down the entire miR-10b population from glioma cells. There is also emerging evidence that RISC components continuously shuttle between the nucleus and cytoplasm (Liu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing

Zhang

Deforzh

et al. 2021

Preprint

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miRNAs are regulatory transcripts established as repressors of mRNA stability and translation. Here we demonstrate that a key onco-miRNA, miR-10b, binds to U6 snRNA, a core component of the spliceosomal machinery. We provide evidence of direct binding between miR-10b and U6, in situ visualizations of miR-10b and U6 co-localization in glioma cells and patient-derived tumor tissues, and biochemical co-isolation of miR-10b with the components of the spliceosome. We further demonstrate that miR-10b modulates U6 N-6-adenosine methylation and pseudouridylation, U6 binding to splicing factors SART3 and PRPF8, and regulates U6 stability, conformation, and levels. These effects on U6 result in splicing alterations, illustrated by the altered ratio of the isoforms of a small GTPase CDC42, reduced overall CDC42 levels, and downstream CDC42 -mediated effects on cell viability. We, therefore, present an unexpected intersection of the miRNA and splicing machineries and a new nuclear function for a major cancer-associated miRNA.

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Section: Mir-10b Binds To Snrna U6 In Glioma Cellsmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing

Zhang

Deforzh

et al. 2021

Preprint

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“…To explore the relevance of circRNA and GBM progression, we analyzed an online‐available dataset (GSE146463 37 ). The results revealed that several circRNAs were differentially expressed between GBM tissues and NC (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Circular RNA circ_0001588 sponges miR‐211‐5p to facilitate the progression of glioblastoma via up‐regulating YY1 expression

Wang

Zheng

et al. 2021

The Journal of Gene Medicine

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Background As the most common and detrimental brain tumor with high invasiveness and poor prognosis, glioblastoma (GBM) has severely threatened people's health globally. Therefore, it is of great importance and necessary to identify the molecular mechanisms involved in tumorigenesis and development, thus contributing to potential therapeutic targets and strategies. Methods The level of circ_0001588 was detected in 68 pairs of GBM tissues and adjacent normal tissues and human glioma cell lines via a real‐time quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR). Then, the effect of circ_0001588 on the proliferation, migration and invasion of glioma cells was evaluated. In addition, potential downstream targets of circ_0001588 were forecasted by circBANK and Starbase. Their interaction was confirmed by introducing luciferase reporter assays. Moreover, sh‐circ_0001588 transfected U251 cells were used to form tumors in vivo. Finally, the functional mechanism of circ_0001588 was identified by qRT‐PCR, western blotting, xenograft and immunohistochemistry (IHC) assays. Results The expression of circ_0001588 is markedly up‐regulated in GBM tissues and human gliomas cells. Additionally, increased expression of circ_0001588 is positively relevant with poor survival in GBM patients. The down‐regulation of circ_0001588 distinctly inhibits the proliferation, migration and invasion of GBM in vitro, as well as tumor growth in vivo. Moreover, knockdown of circ_0001588 reduces the tumor volume and weight, enhances the relative IHC staining index of E‐cadherin and decreases the relative IHC staining index of Ki‐67, Yin Yang 1 (YY1) and vinmentin in vivo. Mechanistically, circ_0001588 locates in the cytoplasm, which is directly bound with miR‐211‐5p. Furthermore, circ_0001588 can positively regulate YY1 via sponging miR‐211‐5p. Moreover, circ_0001588 accelerates the proliferation, migration and invasion of GBM by modulating miR‐211‐5p/YY1 signaling. Conclusions These results illustrate a new circ_0001588/miR‐211‐5p/YY1 regulatory signaling axis in GBM.

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“…It is reported that compared with the normal brain, a variety of tumor-suppressive miRNAs of glioblastoma is signi cantly down-regulated. However, the mechanism is still not clear (19). In the present study, we sequenced the CSF exosomes and matched tumor tissue samples from 59 patients.…”

Section: Introductionmentioning

confidence: 90%

The Double Face of Glioma Exosomal microRNAs: Glioma Eliminates Tumor Suppressor miR-1298-5p via Exosomes to Promote Immunosuppressive Effects of MDSCs

Hao

Jin

et al. 2021

Preprint

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Background: Clear evidence shows that tumor could secrete microRNAs (miRNAs) via exosomes to modulate tumor microenvironment (TME). However, the mechanisms sorting specific miRNAs into exosomes are still unclear. Methods: In order to study the biological function and characterization of exosomal miRNAs, we performed whole-transcriptome sequencing in 59 patients’ whole course cerebrospinal fluid (CSF) small extracellular vesicles (sEV) and matched glioma tissue samples. Results: The results demonstrate that miRNAs could be divided into exosome-enriched miRNAs (ExomiRNAs) and intracellular-retained miRNAs (CLmiRNAs), and exosome-enriched miRNAs generally play a dual role. Among them, miR-1298-5p was enriched in CSF exosomes and suppressed glioma progression in vitro and vivo experiments. Interestingly, exosomal miR-1298-5p could promote Immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) to facilitate glioma. Therefore, we found miR-1298-5p had different effects on glioma cells and MDSCs. Mechanically, downstream signaling pathway analyses showed that miR-1298-5p plays distinct roles in glioma cells and MDSCs via targeting SETD7 and MSH2, respectively. Moreover, reverse verification was performed on the intracellular-retained miRNA miR-9-5p. Conclusions: Thus, we hypothesized that tumor-suppressive miRNAs in glioma cells could be eliminated through exosomes and target tumor-associated immune cells to induce tumor-promoting phenotypes. Glioma could get double benefit from it. These findings uncover the mechanisms that glioma selectively sorts miRNAs into exosomes and modulates tumor immunity.

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The nuclear DICER–circular RNA complex drives the deregulation of the glioblastoma cell microRNAome

Cited by 40 publications

References 54 publications

A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing

A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing

Circular RNA circ_0001588 sponges miR‐211‐5p to facilitate the progression of glioblastoma via up‐regulating YY1 expression

The Double Face of Glioma Exosomal microRNAs: Glioma Eliminates Tumor Suppressor miR-1298-5p via Exosomes to Promote Immunosuppressive Effects of MDSCs

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