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NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma

Oncogene volume 39, pages 891–904 (2020)Cite this article

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Abstract

Circular RNAs (circRNAs) are a novel class of RNAs, which involve in many physiological processes and participate in many diseases, especially in cancer. Previous reports showed circRNAs were globally downregulated in hepatocellular carcinoma (HCC) and a lot of circRNAs involved in the tumorigenesis and metastasis of HCC. To understand the underlying mechanism of circRNAs’ reduction, we explored the relationship between circRNA biogenesis and NUDT21, which was a RNA splice factor downregulated in HCC, and we found that NUDT21 elevated the formation of circRNA, and the UGUA sequences were critical for the cyclization of circRNA. Knockdown of NUDT21 disrupted the competitive endogenous RNA (ceRNA) pathway of circRNA-miRNA-mRNA, and overexpression of the downregulated circRNA could assist the NUDT21-mediated tumor suppression in HCC cells. In conclusion, the loss of NUDT21 prevented the cyclization of circRNA in HCC; without circRNA absorption, miRNAs were released to suppress the tumor-suppressor genes, leading to the uncontrolled cell proliferation.

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References

  1. El-Serag HB. Hepatocellular carcinoma. New Engl J Med. 2011;365:1118–27.

    Article  CAS  Google Scholar 

  2. Zhang H, Sheng C, Yin Y, Wen S, Yang G, Cheng Z, et al. PABPC1 interacts with AGO2 and is responsible for the microRNA mediated gene silencing in high grade hepatocellular carcinoma. Cancer Lett. 2015;367:49–57.

    Article  CAS  Google Scholar 

  3. Greene J, Baird AM, Brady L, Lim M, Gray SG, McDermott R, et al. Circular RNAs: biogenesis, function and role in human diseases. Front Mol Biosci. 2017;4:38.

    Article  Google Scholar 

  4. Ding J, Zhou W, Li X, Sun M, Ding J, Zhu Q. Tandem DNAzyme for double digestion: a new tool for circRNA suppression. Biol Chem. 2019;400:247–53.

    Article  CAS  Google Scholar 

  5. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.

    Article  CAS  Google Scholar 

  6. Wilusz JE, Sharp PA. Molecular biology. A circuitous route to noncoding RNA. Science. 2013;340:440–1.

    Article  CAS  Google Scholar 

  7. Meng X, Chen Q, Zhang P, Chen M. CircPro: an integrated tool for the identification of circRNAs with protein-coding potential. Bioinformatics. 2017;33:3314–6.

    Article  CAS  Google Scholar 

  8. Xu S, Zhou L, Ponnusamy M, Zhang L, Dong Y, Zhang Y, et al. A comprehensive review of circRNA: from purification and identification to disease marker potential. PeerJ. 2018;6:e5503.

    Article  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, et al. Correlation of circular RNA abundance with proliferation-exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis, and normal human tissues. Sci Rep. 2015;5:8057.

    Article  CAS  Google Scholar 

  11. Song C, Li D, Liu H, Sun H, Liu Z, Zhang L, et al. The competing endogenous circular RNA ADAMTS14 suppressed hepatocellular carcinoma progression through regulating microRNA-572/regulator of calcineurin 1. J Cell Physiol. 2019;234:2460–70.

    Article  CAS  Google Scholar 

  12. Zhang XW, Luo P, Jing W, Zhou H, Liang CZ, Tu JC. circSMAD2 inhibits the epithelial-mesenchymal transition by targeting miR-629 in hepatocellular carcinoma. Oncotargets Ther. 2018;11:2853–63.

    Article  Google Scholar 

  13. Han D, Li J, Wang H, Su X, Hou J, Gu Y, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology. 2017;66:1151–64.

    Article  CAS  Google Scholar 

  14. Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365:141–8.

    Article  CAS  Google Scholar 

  15. Kelly S, Greenman C, Cook PR, Papantonis A. Exon skipping is correlated with exon circularization. J Mol Biol. 2015;427:2414–7.

    Article  CAS  Google Scholar 

  16. Zhang XO, Wang HB, Zhang Y, Lu XH, Chen LL, Yang L. Complementary sequence-mediated exon circularization. Cell. 2014;159:134–47.

    Article  CAS  Google Scholar 

  17. Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, et al. The RNA binding protein quaking regulates formation of circRNAs. Cell. 2015;160:1125–34.

    Article  CAS  Google Scholar 

  18. Liang D, Tatomer DC, Luo Z, Wu H, Yang L, Chen LL, et al. The output of protein-coding genes shifts to circular RNAs when the pre-mRNA processing machinery is limiting. Mol Cell. 2017;68:940–54 e3.

    Article  CAS  Google Scholar 

  19. Ashwal-Fluss R, Meyer M, Pamudurti NR, Ivanov A, Bartok O, Hanan M, et al. circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014;56:55–66.

    Article  CAS  Google Scholar 

  20. Kramer MC, Liang DM, Tatomer DC, Gold B, March ZM, Cherry S, et al. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Gene Dev. 2015;29:2168–82.

    Article  CAS  Google Scholar 

  21. Verheijen BM, Pasterkamp RJ. Commentary: FUS affects circular RNA expression in murine embryonic stem cell-derived motor neurons. Front Mol Neurosci. 2017;10:412.

    Article  Google Scholar 

  22. Brown KM, Gilmartin GM. A mechanism for the regulation of pre-mRNA 3’ processing by human cleavage factor Im. Mol Cell. 2003;12:1467–76.

    Article  CAS  Google Scholar 

  23. Yang Q, Coseno M, Gilmartin GM, Doublie S. Crystal structure of a human cleavage factor CFI(m)25/CFI(m)68/RNA complex provides an insight into poly(A) site recognition and RNA looping. Structure. 2011;19:368–77.

    Article  CAS  Google Scholar 

  24. Kubo T, Wada T, Yamaguchi Y, Shimizu A, Handa H. Knock-down of 25 kDa subunit of cleavage factor Im in Hela cells alters alternative polyadenylation within 3’-UTRs. Nucleic Acids Res. 2006;34:6264–71.

    Article  CAS  Google Scholar 

  25. Tan S, Li H, Zhang W, Shao Y, Liu Y, Guan H, et al. NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression. Oncogene. 2018;37:4887–900.

    Article  CAS  Google Scholar 

  26. Sun M, Ding J, Li D, Yang G, Cheng Z, Zhu Q. NUDT21 regulates 3’-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. Cancer Lett. 2017;410:158–68.

    Article  CAS  Google Scholar 

  27. Park HJ, Ji P, Kim S, Xia Z, Rodriguez B, Li L, et al. 3’ UTR shortening represses tumor-suppressor genes in trans by disrupting ceRNA crosstalk. Nat Genet. 2018;50:783–9.

    Article  CAS  Google Scholar 

  28. Lin Y, Li Z, Ozsolak F, Kim SW, Arango-Argoty G, Liu TT, et al. An in-depth map of polyadenylation sites in cancer. Nucleic Acids Res. 2012;40:8460–71.

    Article  CAS  Google Scholar 

  29. Xia Z, Donehower LA, Cooper TA, Neilson JR, Wheeler DA, Wagner EJ, et al. Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3’-UTR landscape across seven tumour types. Nat Commun. 2014;5:5274.

    Article  CAS  Google Scholar 

  30. Zhong YX, Du YJ, Yang X, Mo YZ, Fan CM, Xiong F, et al. Circular RNAs function as ceRNAs to regulate and control human cancer progression. Mol Cancer. 2018;17:79.

    Article  Google Scholar 

  31. Fu L, Yao T, Chen Q, Mo X, Hu Y, Guo J. Screening differential circular RNA expression profiles reveals hsa_circ_0004018 is associated with hepatocellular carcinoma. Oncotarget. 2017;8:58405–16.

    PubMed  PubMed Central  Google Scholar 

  32. Yu J, Xu QG, Wang ZG, Yang Y, Zhang L, Ma JZ, et al. Circular RNA cSMARCA5 inhibits growth and metastasis in hepatocellular carcinoma. J Hepatol. 2018;68:1214–27.

    Article  CAS  Google Scholar 

  33. Wang Y, Wang Z. Efficient backsplicing produces translatable circular mRNAs. RNA. 2015;21:172–9.

    Article  CAS  Google Scholar 

  34. Lin X, Chen Y. Identification of potentially functional CircRNA-miRNA-mRNA regulatory network in hepatocellular carcinoma by integrated microarray analysis. Med Sci Monit Basic Res. 2018;24:70–8.

    Article  Google Scholar 

  35. Gao B, Gao KJ, Li L, Huang ZC, Lin L. miR-184 functions as an oncogenic regulator in hepatocellular carcinoma (HCC). Biomed Pharmacother. 2014;68:143–8.

    Article  CAS  Google Scholar 

  36. Kristensen LS, Hansen TB, Veno MT, Kjems J. Circular RNAs in cancer: opportunities and challenges in the field. Oncogene. 2018;37:555–65.

    Article  CAS  Google Scholar 

  37. Yao R, Zou H, Liao W. Prospect of circular RNA in hepatocellular carcinoma: a novel potential biomarker and therapeutic target. Front Oncol. 2018;8:332.

    Article  Google Scholar 

  38. Li P, Sheng C, Huang L, Zhang H, Huang L, Cheng Z, et al. MiR-183/-96/-182 cluster is up-regulated in most breast cancers and increases cell proliferation and migration. Breast Cancer Res. 2014;16:473.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the KangChen Bio-tech (Shanghai, China) for providing RNA sequencing and data analysis and the Molecular Medical Center in the Xiangya Hospital (Changsha, China) for the confocal microscopy. We thank Shifu Luo for data analysis. We also thank Dr Wang for kindly supplying the IRES-drived pCircGFP reporter. This research is supported by the National Natural Science Foundation of China (C0709-31201056), the Hunan Provincial Natural Science Foundation of China (2018JJ2493) and the Hunan Provincial Innovation Foundation for Postgraduate (CX20190244).

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  1. Xiangya School of Pharmaceutical Sciences in Central South University, Changsha, 410013, Hunan, China

    Xiaojing Li, Junyao Ding, Xueying Wang, Zeneng Cheng & Qubo Zhu

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  1. Xiaojing Li
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Li, X., Ding, J., Wang, X. et al. NUDT21 regulates circRNA cyclization and ceRNA crosstalk in hepatocellular carcinoma. Oncogene 39, 891–904 (2020). https://doi.org/10.1038/s41388-019-1030-0

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