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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

01-12-2021 | Cervical Cancer | Research

The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex

Authors: Mingyi Zhou, Zhuo Yang, Danbo Wang, Peng Chen, Yong Zhang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

As a novel type of non-coding RNA, circular RNAs (circRNAs) play a critical role in the initiation and development of various diseases, including cancer. However, the exact function of circRNAs in human cervical cancer remains largely unknown.

Methods

We identified the circRNA signature of upregulated circRNAs between cervical cancer and paired adjacent normal tissues. Using two different cohorts and GEO database, a total of six upregulated circRNAs were identified with a fold change > 2, and P < 0.05. Among these six circRNAs, hsa_circ_0072088 (circZFR) was the only exonic circRNA significantly overexpressed in cervical cancer. Functional experiments were performed to investigate the biological function of circZFR. CircRNA pull-down, circRNA immunoprecipitation (circRIP) and Co-immunoprecipitation (Co-IP) assays were executed to investigate the molecular mechanism underlying the function of circZFR.

Results

Functionally, circZFR knockdown represses the proliferation, invasion, and tumor growth. Furthermore, circRNA pull-down experiments combined with mass spectrometry unveil the interactions of circZFR with Single-Stranded DNA Binding Protein 1 (SSBP1). Mechanistically, circZFR bound with SSBP1, thereby promoting the assembly of CDK2/cyclin E1 complexes. The activation of CDK2/cyclin E1 complexes induced p-Rb phosphorylation, thus releasing activated E2F1 leading to cell cycle progression and cell proliferation.

Conclusion

Our findings provide the first evidence that circZFR is a novel onco-circRNA and might be a potential biomarker and therapeutic target for cervical cancer patients.
Appendix
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Literature
1.
2.
Lei J, Andrae B, Ploner A, Lagheden C, Eklund C, Nordqvist Kleppe S, Wang J, Fang F, Dillner J, Elfstrom KM, Sparen P. Cervical screening and risk of adenosquamous and rare histological types of invasive cervical carcinoma: population based nested case-control study. BMJ. 2019;365:l1207.PubMedPubMedCentralCrossRef
3.
Canfell K, Kim JJ, Brisson M, Keane A, Simms KT, Caruana M, Burger EA, Martin D, Nguyen DTN, Benard E, et al. Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries. Lancet. 2020;395:591–603.PubMedPubMedCentralCrossRef
4.
Fidler MM, Gupta S, Soerjomataram I, Ferlay J, Steliarova-Foucher E, Bray F. Cancer incidence and mortality among young adults aged 20-39 years worldwide in 2012: a population-based study. Lancet Oncol. 2017;18:1579–89.PubMedCrossRef
5.
6.
Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.PubMedCrossRef
7.
Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016;17:205–11.PubMedCrossRef
8.
Nigro JM, Cho KR, Fearon ER, Kern SE, Ruppert JM, Oliner JD, Kinzler KW, Vogelstein B. Scrambled exons. Cell. 1991;64:607–13.PubMedCrossRef
9.
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
10.
Castello A, Fischer B, Eichelbaum K, Horos R, Beckmann BM, Strein C, Davey NE, Humphreys DT, Preiss T, Steinmetz LM, et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell. 2012;149:1393–406.PubMedCrossRef
11.
Wang ZL, Li B, Luo YX, Lin Q, Liu SR, Zhang XQ, Zhou H, Yang JH, Qu LH. Comprehensive genomic characterization of RNA-binding proteins across human cancers. Cell Rep. 2018;22:286–98.PubMedCrossRef
12.
13.
14.
Chuang TJ, Wu CS, Chen CY, Hung LY, Chiang TW, Yang MY. NCLscan: accurate identification of non-co-linear transcripts (fusion, trans-splicing and circular RNA) with a good balance between sensitivity and precision. Nucleic Acids Res. 2016;44:e29.PubMedCrossRef
15.
Enuka Y, Lauriola M, Feldman ME, Sas-Chen A, Ulitsky I, Yarden Y. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 2016;44:1370–83.PubMedCrossRef
16.
Rybak-Wolf A, Stottmeister C, Glazar P, Jens M, Pino N, Giusti S, Hanan M, Behm M, Bartok O, Ashwal-Fluss R, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed. Mol Cell. 2015;58:870–85.PubMedCrossRef
17.
Wang S, Pan Y, Zhang R, Xu T, Wu W, Zhang R, Wang C, Huang H, Calin CA, Yang H, Claret FX. Hsa-miR-24-3p increases nasopharyngeal carcinoma radiosensitivity by targeting both the 3'UTR and 5'UTR of Jab1/CSN5. Oncogene. 2016;35:6096–108.PubMedPubMedCentralCrossRef
18.
Yuan JH, Liu XN, Wang TT, Pan W, Tao QF, Zhou WP, Wang F, Sun SH. The MBNL3 splicing factor promotes hepatocellular carcinoma by increasing PXN expression through the alternative splicing of lncRNA-PXN-AS1. Nat Cell Biol. 2017;19:820–32.PubMedCrossRef
19.
Pan Y, Zhang Q, Tian L, Wang X, Fan X, Zhang H, Claret FX, Yang H. Jab1/CSN5 negatively regulates p27 and plays a role in the pathogenesis of nasopharyngeal carcinoma. Cancer Res. 2012;72:1890–900.PubMedPubMedCentralCrossRef
20.
Pan Y, Wang S, Su B, Zhou F, Zhang R, Xu T, Zhang R, Leventaki V, Drakos E, Liu W, Claret FX. Stat3 contributes to Cancer progression by regulating Jab1/Csn5 expression. Oncogene. 2017;36:1069–79.PubMedCrossRef
21.
Pan Y, Zhang Q, Atsaves V, Yang H, Claret FX. Suppression of Jab1/CSN5 induces radio- and chemo-sensitivity in nasopharyngeal carcinoma through changes to the DNA damage and repair pathways. Oncogene. 2013;32:2756–66.PubMedCrossRef
22.
Bertrand E, Chartrand P, Schaefer M, Shenoy SM, Singer RH, Long RM. Localization of ASH1 mRNA particles in living yeast. Mol Cell. 1998;2:437–45.PubMedCrossRef
23.
Holdt LM, Stahringer A, Sass K, Pichler G, Kulak NA, Wilfert W, Kohlmaier A, Herbst A, Northoff BH, Nicolaou A, et al. Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016;7:12429.PubMedPubMedCentralCrossRef
24.
Liu J, Wang D, Long Z, Liu J, Li W. CircRNA8924 promotes cervical Cancer cell proliferation, migration and invasion by competitively binding to MiR-518d-5p /519-5p family and modulating the expression of CBX8. Cell Physiol Biochem. 2018;48:173–84.PubMedCrossRef
25.
Jiao J, Zhang T, Jiao X, Huang T, Zhao L, Ma D, Cui B. hsa_circ_0000745 promotes cervical cancer by increasing cell proliferation, migration, and invasion. J Cell Physiol. 2020;235:1287–95.PubMedCrossRef
26.
Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi KA, Benner C, Garcia-Bassets I, Aggarwal AK, et al. PHF8 mediates histone H4 lysine 20 Demethylation events involved in cell cycle progression. Nature. 2010;466:508–12.PubMedPubMedCentralCrossRef
27.
Gertz J, Savic D, Varley KE, Partridge EC, Safi A, Jain P, Cooper GM, Reddy TE, Crawford GE, Myers RM. Distinct properties of cell type-specific and shared transcription factor binding sites. Mol Cell. 2013;52:25–36.
28.
29.
Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000;14:2393–409.PubMedCrossRef
30.
DeCaprio JA, Furukawa Y, Ajchenbaum F, Griffin JD, Livingston DM. The retinoblastoma-susceptibility gene product becomes phosphorylated in multiple stages during cell cycle entry and progression. Proc Natl Acad Sci U S A. 1992;89:1795–8.PubMedPubMedCentralCrossRef
31.
32.
Kaye FJ, Kratzke RA, Gerster JL, Horowitz JM. A single amino acid substitution results in a retinoblastoma protein defective in phosphorylation and oncoprotein binding. Proc Natl Acad Sci U S A. 1990;87:6922–6.PubMedPubMedCentralCrossRef
33.
34.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.PubMedCrossRef
35.
Ou R, Mo L, Tang H, Leng S, Zhu H, Zhao L, Ren Y, Xu Y. circRNA-AKT1 sequesters miR-942-5p to Upregulate AKT1 and promote cervical Cancer progression. Mol Ther Nucleic Acids. 2020;20:308–22.PubMedPubMedCentralCrossRef
36.
Ji F, Du R, Chen T, Zhang M, Zhu Y, Luo X, Ding Y. Circular RNA circSLC26A4 accelerates cervical Cancer progression via miR-1287-5p/HOXA7 Axis. Mol Ther Nucleic Acids. 2020;19:413–20.PubMedCrossRef
37.
Yang X, Liu L, Zou H, Zheng YW, Wang KP. circZFR promotes cell proliferation and migration by regulating miR-511/AKT1 axis in hepatocellular carcinoma. Dig Liver Dis. 2019;51:1446–55.PubMedCrossRef
38.
Li H, Liu F, Qin W. Circ_0072083 interference enhances growth-inhibiting effects of cisplatin in non-small-cell lung cancer cells via miR-545-3p/CBLL1 axis. Cancer Cell Int. 2020;20:78.PubMedPubMedCentralCrossRef
39.
40.
Yao G, Lee TJ, Mori S, Nevins JR, You L. A bistable Rb-E2F switch underlies the restriction point. Nat Cell Biol. 2008;10:476–82.PubMedCrossRef
41.
Lee C, Chang JH, Lee HS, Cho Y. Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor. Genes Dev. 2002;16:3199–212.PubMedPubMedCentralCrossRef
42.
Xiao B, Spencer J, Clements A, Ali-Khan N, Mittnacht S, Broceno C, Burghammer M, Perrakis A, Marmorstein R, Gamblin SJ. Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation. Proc Natl Acad Sci U S A. 2003;100:2363–8.PubMedPubMedCentralCrossRef
43.
Adams PD, Li X, Sellers WR, Baker KB, Leng X, Harper JW, Taya Y, Kaelin WG Jr. Retinoblastoma protein contains a C-terminal motif that targets it for phosphorylation by cyclin-cdk complexes. Mol Cell Biol. 1999;19:1068–80.PubMedPubMedCentralCrossRef
44.
Schulman BA, Lindstrom DL, Harlow E. Substrate recruitment to cyclin-dependent kinase 2 by a multipurpose docking site on cyclin a. Proc Natl Acad Sci U S A. 1998;95:10453–8.PubMedPubMedCentralCrossRef
45.
Zarkowska T, Mittnacht S. Differential phosphorylation of the retinoblastoma protein by G1/S cyclin-dependent kinases. J Biol Chem. 1997;272:12738–46.PubMedCrossRef
46.
Knudsen ES, Wang JY. Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites. J Biol Chem. 1996;271:8313–20.PubMedCrossRef
47.
Rubin SM. Deciphering the retinoblastoma protein phosphorylation code. Trends Biochem Sci. 2013;38:12–9.PubMedCrossRef
48.
Burke JR, Hura GL, Rubin SM. Structures of inactive retinoblastoma protein reveal multiple mechanisms for cell cycle control. Genes Dev. 2012;26:1156–66.PubMedPubMedCentralCrossRef
49.
Burke JR, Deshong AJ, Pelton JG, Rubin SM. Phosphorylation-induced conformational changes in the retinoblastoma protein inhibit E2F transactivation domain binding. J Biol Chem. 2010;285:16286–93.PubMedPubMedCentralCrossRef
50.
Li Q, Wang Y, Wu S, Zhou Z, Ding X, Shi R, Thorne RF, Zhang XD, Hu W, Wu M. CircACC1 regulates assembly and activation of AMPK complex under metabolic stress. Cell Metab. 2019;30:157–73 e157.PubMedCrossRef
51.
Wang L, Long H, Zheng Q, Bo X, Xiao X, Li B. Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression. Mol Cancer. 2019;18:119.PubMedPubMedCentralCrossRef
52.
Zhu YJ, Zheng B, Luo GJ, Ma XK, Lu XY, Lin XM, Yang S, Zhao Q, Wu T, Li ZX, et al. Circular RNAs negatively regulate cancer stem cells by physically binding FMRP against CCAR1 complex in hepatocellular carcinoma. Theranostics. 2019;9:3526–40.PubMedPubMedCentralCrossRef
53.
Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44:2846–58.PubMedPubMedCentralCrossRef
54.
Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–34.PubMedCrossRef
Metadata
Title
The circular RNA circZFR phosphorylates Rb promoting cervical cancer progression by regulating the SSBP1/CDK2/cyclin E1 complex
Authors
Mingyi Zhou
Zhuo Yang
Danbo Wang
Peng Chen
Yong Zhang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01849-2

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