The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68

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Abstract

Background

Long non-coding RNAs (lncRNAs) function as key molecules in cancer progression. The lncRNA CYTOR plays oncogenic roles in multiple types of cancer, yet the detailed molecular mechanisms of those roles remain unknown. The aim of this study was to investigate the clinical significance, biological function and interacting partners of CYTOR in colorectal cancer (CRC).

Methods

A systematic and comprehensive analysis of CYTOR expression was performed in 138 CRC samples and in the TCGA and GEO databases. Biological function was investigated through knockdown and overexpression of CYTOR in vitro and in vivo. In addition, its protein binding partner was identified and validated using ChIRP-MS and RNA immunoprecipitation assays. Their key interaction sites on CYTOR were verified by CRISPR/Cas9 and a series of mutant constructs. Furthermore, the downstream targets of CYTOR were confirmed via immunoblotting and luciferase reporter assays.

Results

CYTOR was significantly up-regulated in CRC samples and associated with poor prognosis, promoting proliferation and metastasis in vitro and in vivo. NCL and Sam68 could recognize their specific motifs and directly bind to EXON1 of CYTOR. Moreover, EXON1 was the key functional site mediating the interaction of CYTOR with NCL and Sam68. NCL and Sam68 functioned as oncogenes to promote CRC progression. Furthermore, we confirmed that the heterotrimeric complex of CYTOR, NCL and Sam68 activated the NF-κB pathway and EMT to contribute to CRC progression.

Conclusion

CYTOR plays important roles in CRC progression by interacting with NCL and Sam68 and may serve as a prognostic biomarker and/or an effective target for CRC therapies.

Electronic supplementary material

The online version of this article (10.1186/s12943-018-0860-7) contains supplementary material, which is available to authorized users.

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Most cited references 25

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Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

Cristian Tomasetti, Lu Li, Bert Vogelstein (2017)

Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations.

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Regulation of transcription by long noncoding RNAs.

Roberto Bonasio, Ramin Shiekhattar (2014)

Over the past decade there has been a greater understanding of genomic complexity in eukaryotes ushered in by the immense technological advances in high-throughput sequencing of DNA and its corresponding RNA transcripts. This has resulted in the realization that beyond protein-coding genes, there are a large number of transcripts that do not encode for proteins and, therefore, may perform their function through RNA sequences and/or through secondary and tertiary structural determinants. This review is focused on the latest findings on a class of noncoding RNAs that are relatively large (>200 nucleotides), display nuclear localization, and use different strategies to regulate transcription. These are exciting times for discovering the biological scope and the mechanism of action for these RNA molecules, which have roles in dosage compensation, imprinting, enhancer function, and transcriptional regulation, with a great impact on development and disease.

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Is Open Access

Chromatin Isolation by RNA Purification (ChIRP)

Ci Chu, Jeffrey Quinn, Howard Y. Chang (2012)

Long noncoding RNAs are key regulators of chromatin states for important biological processes such as dosage compensation, imprinting, and developmental gene expression 1,2,3,4,5,6,7. The recent discovery of thousands of lncRNAs in association with specific chromatin modification complexes, such as Polycomb Repressive Complex 2 (PRC2) that mediates histone H3 lysine 27 trimethylation (H3K27me3), suggests broad roles for numerous lncRNAs in managing chromatin states in a gene-specific fashion 8,9. While some lncRNAs are thought to work in cis on neighboring genes, other lncRNAs work in trans to regulate distantly located genes. For instance, Drosophila lncRNAs roX1 and roX2 bind numerous regions on the X chromosome of male cells, and are critical for dosage compensation 10,11. However, the exact locations of their binding sites are not known at high resolution. Similarly, human lncRNA HOTAIR can affect PRC2 occupancy on hundreds of genes genome-wide 3,12,13, but how specificity is achieved is unclear. LncRNAs can also serve as modular scaffolds to recruit the assembly of multiple protein complexes. The classic trans-acting RNA scaffold is the TERC RNA that serves as the template and scaffold for the telomerase complex 14; HOTAIR can also serve as a scaffold for PRC2 and a H3K4 demethylase complex 13. Prior studies mapping RNA occupancy at chromatin have revealed substantial insights 15,16, but only at a single gene locus at a time. The occupancy sites of most lncRNAs are not known, and the roles of lncRNAs in chromatin regulation have been mostly inferred from the indirect effects of lncRNA perturbation. Just as chromatin immunoprecipitation followed by microarray or deep sequencing (ChIP-chip or ChIP-seq, respectively) has greatly improved our understanding of protein-DNA interactions on a genomic scale, here we illustrate a recently published strategy to map long RNA occupancy genome-wide at high resolution 17. This method, Chromatin Isolation by RNA Purification (ChIRP) (Figure 1), is based on affinity capture of target lncRNA:chromatin complex by tiling antisense-oligos, which then generates a map of genomic binding sites at a resolution of several hundred bases with high sensitivity and low background. ChIRP is applicable to many lncRNAs because the design of affinity-probes is straightforward given the RNA sequence and requires no knowledge of the RNA's structure or functional domains.

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Author and article information

Contributors

Xue Wang: mzby_111@163.com

Hongfei Yu: yuhongfei95@163.com

Wenjie Sun: sunwenjie@zju.edu.cn

Jianlu Kong: kongjianlu@sina.com

Lei Zhang: mousha742@163.com

Jinlong Tang: 21018274@zju.edu.cn

Jingyu Wang: 11018140@zju.edu.cn

Enping Xu: xep@zju.edu.cn

Maode Lai: lmp@zju.edu.cn

Honghe Zhang: honghezhang@zju.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 31 July 2018

Publication date PMC-release: 31 July 2018

Publication date Collection: 2018

Volume: 17

Electronic Location Identifier: 110

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, , Zhejiang University School of Medicine, ; Hangzhou, 310058 China

[2 ]ISNI 0000 0000 9776 7793, GRID grid.254147.1, Department of Pharmacology, , China Pharmaceutical University, ; Nanjing, 210009 China

Article

Publisher ID: 860

DOI: 10.1186/s12943-018-0860-7

PMC ID: 6069835

PubMed ID: 30064438

SO-VID: 9b0fea79-718e-46c9-b14c-80403e12a90e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 24 November 2017

Date accepted : 20 July 2018

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer,cytor,ncl,sam68

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: colorectal cancer, cytor, ncl, sam68

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The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

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Karger: Oncology

Most cited references 25

Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

Regulation of transcription by long noncoding RNAs.

Chromatin Isolation by RNA Purification (ChIRP)

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Cited by 66

Most referenced authors 555