Upregulated long non-coding RNA AGAP2-AS1 represses LATS2 and KLF2 expression through interacting with EZH2 and LSD1 in non-small-cell lung cancer cells

Abstract

Recently, long non-coding RNAs (lncRNAs) are identified as new crucial regulators of diverse cellular processes, including cell proliferation, differentiation and cancer cells metastasis. Accumulating evidence has revealed that aberrant lncRNA expression plays important roles in carcinogenesis and tumor progression. However, the expression pattern and biological function of lncRNAs in non-small-cell lung cancer (NSCLC) remain largely unknown. In this study, we performed comprehensive analysis of lncRNA expression in human NSCLC samples by using microarray data from Gene Expression Omnibus. After validation in a cohort of 80 pairs of NSCLC tissues, we identified a differentially expressed novel oncogenic lncRNA termed as AGAP2-AS1. The AGAP2-AS1 expression level was significantly upregulated in NSCLC tissues and negatively correlated with poor prognostic outcomes in patients. In vitro loss- and gain-of-function assays revealed that AGAP2-AS1 knockdown inhibited cell proliferation, migration and invasion, and induced cell apoptosis. In vivo assays also confirmed the ability of AGAP2-AS1 to promote tumor growth. Furthermore, mechanistic investigation showed that AGAP2-AS1 could bind with enhancer of zeste homolog 2 and lysine (K)-specific demethylase 1A, and recruit them to KLF2 and LATS2 promoter regions to repress their transcription. Taken together, our findings indicate that AGAP2-AS1 may act as an oncogene by repressing tumor-suppressor LATS2 and KLF2 transcription. By clarifying the AGAP2-AS1 mechanisms underlying NSCLC development and progression, these findings might promote the development of novel therapeutic strategies for this disease.

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References 33

1. 1.

   Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30.

   Not in our library10.3322/caac.21166

2. 2.

   Spira A, Ettinger DS. Multidisciplinary management of lung cancer. N Engl J Med 2004; 350: 379–392.

   Not in our library10.1056/nejmra035536

3. 3.

   Verdecchia A, Francisci S, Brenner H, Gatta G, Micheli A, Mangone L et al. Recent cancer survival in Europe: a 2000-02 period analysis of EUROCARE-4 data. Lancet Oncol 2007; 8: 784–796.

   Not in our library10.1016/s1470-2045(07)70246-2

4. 4.

   Wistuba II. Genetics of preneoplasia: lessons from lung cancer. Curr Mol Med 2007; 7: 3–14.

   Not in our library10.2174/156652407779940468

5. 5.

   Fenech M. The Genome Health Clinic and Genome Health Nutrigenomics concepts: diagnosis and nutritional treatment of genome and epigenome damage on an individual basis. Mutagenesis 2005; 20: 255–269.

   Not in our library10.1093/mutage/gei040

6. 6.

   Cooper WA, Lam DC, O'Toole SA, Minna JD. Molecular biology of lung cancer. J Thorac Dis 2013; 5((Suppl 5)): S479–S490.

   Not in our library10.3978/j.issn.2072-1439.2013.08.03

7. 7.

   International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004; 431: 931–945.

   Not in our library10.1038/nature03001

8. 8.

   Griffiths-Jones S. Annotating noncoding RNA genes. Annu Rev Genomics Hum Genet 2007; 8: 279–298.

   Not in our library10.1146/annurev.genom.8.080706.092419

9. 9.

   Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A et al. Landscape of transcription in human cells. Nature 2012; 489: 101–108.

   Not in our library10.1038/nature11233

10. 10.

    Kosik KS. MicroRNAs and cellular phenotypy. Cell 2010; 143: 21–26.

    Not in our library10.1016/j.cell.2010.09.008

11. 11.

    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57–74.

    Not in our library10.1038/nature11247

12. 12.

    Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res 2012; 22: 1760–1774.

    Not in our library10.1101/gr.135350.111

13. 13.

    Ulitsky I, Bartel DP. lincRNAs: genomics, evolution, and mechanisms. Cell 2013; 154: 26–46.

    Not in our library10.1016/j.cell.2013.06.020

14. 14.

    Wilusz JE. Long noncoding RNAs: Re-writing dogmas of RNA processing and stability. Biochim Biophys Acta 2015; 1859: 128–138.

    Not in our library10.1016/j.bbagrm.2015.06.003

15. 15.

    Rinn JL. lncRNAs: linking RNA to chromatin. Cold Spring Harb Perspect Biol 2014; 6: pii: a018614.

    Not in our library10.1101/cshperspect.a018614

16. 16.

    Shi X, Sun M, Liu H, Yao Y, Song Y. Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013; 339: 159–166.

    Not in our library10.1016/j.canlet.2013.06.013

17. 17.
    Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets · 2015

    No notice
18. 18.

    Fan J, Xing Y, Wen X, Jia R, Ni H, He J et al. Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol 2015; 16: 139.

    Not in our library10.1186/s13059-015-0705-2

19. 19.

    Wang TH, Lin YS, Chen Y, Yeh CT, Huang YL, Hsieh TH et al. Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition. Oncotarget 2015; 6: 23342–23357.

    Not in our library10.18632/oncotarget.4344

20. 20.

    Qiu M, Xu Y, Wang J, Zhang E, Sun M, Zheng Y et al. A novel lncRNA, LUADT1, promotes lung adenocarcinoma proliferation via the epigenetic suppression of p27. Cell Death Dis 2015; 6: e1858.

    Not in our library10.1038/cddis.2015.203

21. 21.
    P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression · 2014

    No notice
22. 22.

    Nie FQ, Sun M, Yang JS, Xie M, Xu TP, Xia R et al. Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. Mol Cancer Ther 2015; 14: 268–277.

    Not in our library10.1158/1535-7163.mct-14-0492

23. 23.

    Yin L, Wang JP, Xu TP, Chen WM, Huang MD, Xia R et al. Downregulation of Kruppel-like factor 2 is associated with poor prognosis for nonsmall-cell lung cancer. Tumour Biol 2015; 36: 3075–3084.

    Not in our library10.1007/s13277-014-2943-4

24. 24.

    Khandelwal A, Bacolla A, Vasquez KM, Jain A. Long non-coding RNA: A new paradigm for lung cancer. Mol Carcinog 2015; 54: 1235–1251.

    Not in our library10.1002/mc.22362

25. 25.

    Sun M, Gadad SS, Kim DS, Kraus WL. Discovery, annotation, and functional analysis of long noncoding RNAs controlling cell-cycle gene expression and proliferation in breast cancer cells. Mol Cell 2015; 59: 698–711.

    Not in our library10.1016/j.molcel.2015.06.023

26. 26.

    Cheng Z, Guo J, Chen L, Luo N, Yang W, Qu X. A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer. Oncotarget 2015; 6: 25381–25389.

    Not in our library10.18632/oncotarget.4541

27. 27.

    Shi X, Sun M, Wu Y, Yao Y, Liu H, Wu G et al. Post-transcriptional regulation of long noncoding RNAs in cancer. Tumour Biol 2015; 36: 503–513.

    Not in our library10.1007/s13277-015-3106-y

28. 28.

    Volkel P, Dupret B, Le Bourhis X, Angrand PO. Diverse involvement of EZH2 in cancer epigenetics. Am J Transl Res 2015; 7: 175–193.

    Not in our library

29. 29.

    Shin J, Ming GL, Song H. Molecular toggle switch of histone demethylase LSD1. Mol Cell 2015; 57: 949–950.

    Not in our library10.1016/j.molcel.2015.03.007

30. 30.
    Over-Expression of LSD1 Promotes Proliferation, Migration and Invasion in Non-Small Cell Lung Cancer · 2012

    Expression of concern
31. 31.

    Geng J, Li X, Zhou Z, Wu CL, Dai M, Bai X. EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer. Cancer Lett 2015; 359: 275–287.

    Not in our library10.1016/j.canlet.2015.01.031

32. 32.

    Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S. Kruppel-like transcription factors: a functional family. Int J Biochem Cell Biol 2008; 40: 1996–2001.

    Not in our library10.1016/j.biocel.2007.07.018

33. 33.

    Visser S, Yang X. LATS tumor suppressor: a new governor of cellular homeostasis. Cell Cycle 2010; 9: 3892–3903.

    Not in our library10.4161/cc.9.19.13386

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