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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Gastric Cancer | Research

Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation

Authors: Feng Yang, Anpei Hu, Dan Li, Jianqun Wang, Yanhua Guo, Yang Liu, Hongjun Li, Yajun Chen, Xiaojing Wang, Kai Huang, Liduan Zheng, Qiangsong Tong

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Background

Circular RNAs (circRNAs), a subclass of non-coding RNAs, play essential roles in tumorigenesis and aggressiveness. Our previous study has identified that circAGO2 drives gastric cancer progression through activating human antigen R (HuR), a protein stabilizing AU-rich element-containing mRNAs. However, the functions and underlying mechanisms of circRNAs derived from HuR in gastric cancer progression remain elusive.

Methods

CircRNAs derived from HuR were detected by real-time quantitative RT-PCR and validated by Sanger sequencing. Biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, RNA electrophoretic mobility shift, and in vitro binding assays were applied to identify proteins interacting with circRNA. Gene expression regulation was observed by chromatin immunoprecipitation, dual-luciferase assay, real-time quantitative RT-PCR, and western blot assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its protein partner on the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo.

Results

Circ-HuR (hsa_circ_0049027) was predominantly detected in the nucleus, and was down-regulated in gastric cancer tissues and cell lines. Ectopic expression of circ-HuR suppressed the growth, invasion, and metastasis of gastric cancer cells in vitro and in vivo. Mechanistically, circ-HuR interacted with CCHC-type zinc finger nucleic acid binding protein (CNBP), and subsequently restrained its binding to HuR promoter, resulting in down-regulation of HuR and repression of tumor progression.

Conclusions

Circ-HuR serves as a tumor suppressor to inhibit CNBP-facilitated HuR expression and gastric cancer progression, indicating a potential therapeutic target for gastric cancer.
Appendix
Available only for authorised users
Literature
1.
Van Cutsem E, Sagaert X, Topal B, Haustermans K, Prenen H. Gastric cancer. Lancet. 2016;388:2654–64.PubMedCrossRef
2.
Zucal C, D'Agostino V, Loffredo R, Mantelli B, NatthakanThongon LP, Latorre E, Provenzani A. Targeting the multifaceted HuR protein, benefits and caveats. Curr Drug Targets. 2015;16:499–515.PubMedCrossRef
3.
Doller A, el-S A, Huwiler A, Muller R, Radeke HH, Pfeilschifter J, Eberhardt W. Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol Cell Biol. 2008;28:2608–25.PubMedPubMedCentralCrossRef
4.
Vazquez-Chantada M, Fernandez-Ramos D, Embade N, Martinez-Lopez N, Varela-Rey M, Woodhoo A, Luka Z, Wagner C, Anglim PP, Finnell RH, et al. HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis. Gastroenterology. 2010;138:1943–53.PubMedCrossRef
5.
Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol. 2014;31:161.PubMedCrossRef
6.
Heinonen M, Bono P, Narko K, Chang SH, Lundin J, Joensuu H, Furneaux H, Hla T, Haglund C, Ristimaki A. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma. Cancer Res. 2005;65:2157–61.PubMedCrossRef
7.
Denkert C, Koch I, von Keyserlingk N, Noske A, Niesporek S, Dietel M, Weichert W. Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2. Mod Pathol. 2006;19:1261–9.PubMedCrossRef
8.
Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J, Nordling S, Ristimaki A, Haglund C. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res. 2005;11:7362–8.PubMedCrossRef
9.
Niesporek S, Kristiansen G, Thoma A, Weichert W, Noske A, Buckendahl AC, Jung K, Stephan C, Dietel M, Denkert C. Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression. Int J Oncol. 2008;32:341–7.PubMed
10.
Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu YM, Dhanasekaran SM, Engelke CG, Cao X, et al. The landscape of circular RNA in cancer. Cell. 2019;176:869–81.PubMedCrossRefPubMedCentral
11.
Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.PubMedCrossRef
12.
Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 2013;495:333–8.CrossRefPubMed
13.
14.
Yang Q, Du WW, Wu N, Yang W, Awan FM, Fang L, Ma J, Li X, Zeng Y, Yang Z, et al. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation. Cell Death Differ. 2017;24:1609–20.PubMedPubMedCentralCrossRef
15.
Yang F, Fang E, Mei H, Chen Y, Li H, Li D, Song H, Wang J, Hong M, Xiao W, et al. Cis-acting circ-CTNNB1 promotes β-catenin signaling and cancer progression via DDX3-mediated transactivation of YY1. Cancer Res. 2019;79:557–71.PubMedCrossRef
16.
Li Z, Huang C, Bao C, Chen L, Lin M, Wang X, Zhong G, Yu B, Hu W, Dai L, et al. Exon-intron circular RNAs regulate transcription in the nucleus. Nat Struct Mol Biol. 2015;22:256–64.PubMedCrossRef
17.
Chen Y, Yang F, Fang E, Xiao W, Mei H, Li H, Li D, Song H, Wang J, Hong M, et al. Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes. Cell Death Differ. 2019;26:1346–64.PubMedCrossRef
18.
Li D, Wang X, Mei H, Fang E, Ye L, Song H, Yang F, Li H, Huang K, Zheng L, et al. Long noncoding RNA pancEts-1 promotes neuroblastoma progression through hnRNPK-mediated β-catenin stabilization. Cancer Res. 2018;78:1169–83.PubMedCrossRef
19.
Li D, Song H, Mei H, Fang E, Wang X, Yang F, Li H, Chen Y, Huang K, Zheng L, et al. Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. Nat Commun. 2018;9:2829.PubMedPubMedCentralCrossRef
20.
Xiang X, Mei H, Qu H, Zhao X, Li D, Song H, Jiao W, Pu J, Huang K, Zheng L, et al. miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14. Biochim Biophys Acta. 2015;1852:1743–54.PubMedCrossRef
21.
Zhao X, Li D, Pu J, Mei H, Yang D, Xiang X, Qu H, Huang K, Zheng L, Tong Q. CTCF cooperates with noncoding RNA MYCNOS to promote neuroblastoma progression through facilitating MYCN expression. Oncogene. 2016;35:3565–76.PubMedCrossRef
22.
Sun Q, Tripathi V, Yoon JH, Singh DK, Hao Q, Min KW, Davila S, Zealy RW, Li XL, Polycarpou-Schwarz M, et al. MIR100 host gene-encoded lncRNAs regulate cell cycle by modulating the interaction between HuR and its target mRNAs. Nucleic Acids Res. 2018;46:10405–16.PubMedPubMedCentralCrossRef
23.
Lopez de Silanes I, Fan J, Yang X, Zonderman AB, Potapova O, Pizer ES, Gorospe M. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene. 2003;22:7146–54.PubMedCrossRef
24.
Atasoy U, Watson J, Patel D, Keene JD. ELAV protein HuA (HuR) can redistribute between nucleus and cytoplasm and is upregulated during serum stimulation and T cell activation. J Cell Sci. 1998;111:3145–56.PubMed
25.
Fan XC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J. 1998;17:3448–60.PubMedPubMedCentralCrossRef
26.
Lee E, Lee TA, Kim JH, Park A, Ra EA, Kang S, Choi HJ, Choi JL, Huh HD, Lee JE, et al. CNBP acts as a key transcriptional regulator of sustained expression of interleukin-6. Nucleic Acids Res. 2017;45:3280–96.PubMedPubMedCentralCrossRef
27.
Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginossar N, Brandman O, Whitehead EH, Doudna JA, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154:442–51.PubMedPubMedCentralCrossRef
28.
Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152:1173–83.PubMedPubMedCentralCrossRef
29.
Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH, Guimaraes C, Panning B, Ploegh HL, Bassik MC, et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell. 2014;159:647–61.PubMedPubMedCentralCrossRef
30.
Zheng Y, Shen W, Zhang J, Yang B, Liu YN, Qi H, Yu X, Lu SY, Chen Y, Xu YZ, et al. CRISPR interference-based specific and efficient gene inactivation in the brain. Nat Neurosci. 2018;21:447–54.PubMedCrossRef
31.
Lee E, Lee TA, Yoo HJ, Lee S, Park B. CNBP controls tumor cell biology by regulating tumor-promoting gene expression. Mol Carcinog. 2019;58:1492–501.PubMedCrossRef
32.
Michelotti EF, Tomonaga T, Krutzsch H, Levens D. Cellular nucleic acid binding protein regulates the CT element of the human c-myc protooncogene. J Biol Chem. 1995;270:9494–9.PubMedCrossRef
33.
Salzman J, Gawad C, Wang PL, Lacayo N, Brown PO. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diverse cell types. PLoS One. 2012;7:e30733.PubMedPubMedCentralCrossRef
34.
35.
36.
Huang G, Li S, Yang N, Zou Y, Zheng D, Xiao T. Recent progress in circular RNAs in human cancers. Cancer Lett. 2017;404:8–18.PubMedCrossRef
37.
Ng WL, Mohd Mohidin TB, Shukla K. Functional role of circular RNAs in cancer development and progression. RNA Biol. 2018;15:995–1005.PubMedPubMedCentral
38.
Yang Y, Gao X, Zhang M, Yan S, Sun C, Xiao F, Huang N, Yang X, Zhao K, Zhou H, et al. Novel role of FBXW7 circular RNA in repressing Glioma tumorigenesis. J Natl Cancer Inst. 2018;110:304–15.CrossRef
39.
Wei Y, Chen X, Liang C, Ling Y, Yang X, Ye X, Zhang H, Yang P, Cui X, Ren Y, et al. A noncoding regulatory RNAs network driven by circ-CDYL acts specifically in the early stages hepatocellular carcinoma. Hepatology. 2019. https://​doi.​org/​10.​1002/​hep.​30795.
40.
Zhang Y, Zhang XO, Chen T, Xiang JF, Yin QF, Xing YH, Zhu S, Yang L, Chen LL. Circular intronic long noncoding RNAs. Mol Cell. 2013;51:792–806.PubMedCrossRef
41.
Calcaterra NB, Armas P, Weiner AM, Borgognone M. CNBP: a multifunctional nucleic acid chaperone involved in cell death and proliferation control. IUBMB Life. 2010;62:707–14.PubMedCrossRef
42.
Meisner NC, Hintersteiner M, Mueller K, Bauer R, Seifert JM, Naegeli HU, Ottl J, Oberer L, Guenat C, Moss S, et al. Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR. Nat Chem Biol. 2007;3:508–15.PubMedCrossRef
43.
Konicek BW, Xia X, Rajavashisth T, Harrington MA. Regulation of mouse colony-stimulating factor-1 gene promoter activity by AP1 and cellular nucleic acid-binding protein. DNA Cell Biol. 1998;17:799–809.PubMedCrossRef
44.
D'Amico D, Antonucci L, Di Magno L, Coni S, Sdruscia G, Macone A, Miele E, Infante P, Di Marcotullio L, De Smaele E, et al. Non-canonical hedgehog/AMPK-mediated control of polyamine metabolism supports neuronal and medulloblastoma cell growth. Dev Cell. 2015;35:21–35.PubMedPubMedCentralCrossRef
45.
46.
Mukherjee N, Corcoran DL, Nusbaum JD, Reid DW, Georgiev S, Hafner M, Ascano M Jr, Tuschl T, Ohler U, Keene JD. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell. 2011;43:327–39.PubMedPubMedCentralCrossRef
47.
Levine TD, Gao F, King PH, Andrews LG, Keene JD. Hel-N1: an autoimmune RNA-binding protein with specificity for 3′ uridylate-rich untranslated regions of growth factor mRNAs. Mol Cell Biol. 1993;13:3494–504.PubMedPubMedCentralCrossRef
48.
Pan H, Strickland A, Madhu V, Johnson ZI, Chand SN, Brody JR, Fertala A, Zheng Z, Shapiro IM, Risbud MV. RNA binding protein HuR regulates extracellular matrix gene expression and pH homeostasis independent of controlling HIF-1α signaling in nucleus pulposus cells. Matrix Biol. 2019;77:23–40.PubMedCrossRef
49.
50.
Allegri L, Baldan F, Roy S, Aube J, Russo D, Filetti S, Damante G. The HuR CMLD-2 inhibitor exhibits antitumor effects via MAD2 downregulation in thyroid cancer cells. Sci Rep. 2019;9:7374.PubMedPubMedCentralCrossRef
Metadata
Title
Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation
Authors
Feng Yang
Anpei Hu
Dan Li
Jianqun Wang
Yanhua Guo
Yang Liu
Hongjun Li
Yajun Chen
Xiaojing Wang
Kai Huang
Liduan Zheng
Qiangsong Tong
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-1094-z

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