Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas

  • Authors:
    • Jia Li
    • Er-Bao Bian
    • Xiao-Jun He
    • Chun-Chun Ma
    • Gang Zong
    • Hong-Liang Wang
    • Bing Zhao
  • View Affiliations

  • Published online on: December 10, 2015     https://doi.org/10.3892/ijo.2015.3285
  • Pages: 723-733
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Abstract

Epigenetic regulation plays a significant role in gliomas. However, how methylation and long non-coding RNA (lncRNA) cooperates to regulate gliomas progression is largely unknown. In this investigation we showed that the downregulation of MEG3 expression due to hypermethylation of MEG3 was observed in gliomas tissues. Treatment of glioma cells with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) decreased aberrant hypermethylation of the MEG3 promoter and prevented the loss of MEG3 expression. In addition, DNMT1 was involved in MEG3 promoter methylation, and was inversely correlated with MEG3 expression in gliomas. The inhibition of DNMT1 repressed the proliferation, clone formation, and induced apoptosis in glioma cells. Importantly, the inhibition of DNMT1 contributed to the activation of p53 pathways in gliomas cells. These results suggest that DNMT1-mediated MEG3 hypermethylation caused the loss of MEG3 expression, followed by the inhibition of the p53 pathways in gliomas.

References

1 

Wang Y and Jiang T: Understanding high grade glioma: Molecular mechanism, therapy and comprehensive management. Cancer Lett. 331:139–146. 2013. View Article : Google Scholar : PubMed/NCBI

2 

Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10:459–466. 2009. View Article : Google Scholar : PubMed/NCBI

3 

Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Wilusz JE, Sunwoo H and Spector DL: Long noncoding RNAs: Functional surprises from the RNA world. Genes Dev. 23:1494–1504. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Nagano T and Fraser P: No-nonsense functions for long noncoding RNAs. Cell. 145:178–181. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Wu Y, Zhang L, Zhang L, Wang Y, Li H, Ren X, Wei F, Yu W, Liu T, Wang X, et al: Long non-coding RNA HOTAIR promotes tumor cell invasion and metastasis by recruiting EZH2 and repressing E-cadherin in oral squamous cell carcinoma. Int J Oncol. 46:2586–2594. 2015.PubMed/NCBI

7 

Wang Y, Chen W, Yang C, Wu W, Wu S, Qin X and Li X: Long non-coding RNA UCA1a (CUDR) promotes proliferation and tumorigenesis of bladder cancer. Int J Oncol. 41:276–284. 2012.PubMed/NCBI

8 

Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q, et al: Long noncoding RNAs with enhancer-like function in human cells. Cell. 143:46–58. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Tian D, Sun S and Lee JT: The long noncoding RNA, Jpx, is a molecular switch for X chromosome inactivation. Cell. 143:390–403. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Kobayashi S, Wagatsuma H, Ono R, Ichikawa H, Yamazaki M, Tashiro H, Aisaka K, Miyoshi N, Kohda T, Ogura A, et al: Mouse Peg9/Dlk1 and human PEG9/DLK1 are paternally expressed imprinted genes closely located to the maternally expressed imprinted genes: Mouse Meg3/Gtl2 and human MEG3. Genes Cells. 5:1029–1037. 2000. View Article : Google Scholar

11 

Anwar SL, Krech T, Hasemeier B, Schipper E, Schweitzer N, Vogel A, Kreipe H and Lehmann U: Loss of imprinting and allelic switching at the DLK1-MEG3 locus in human hepatocellular carcinoma. PLoS One. 7:e494622012. View Article : Google Scholar : PubMed/NCBI

12 

Astuti D, Latif F, Wagner K, Gentle D, Cooper WN, Catchpoole D, Grundy R, Ferguson-Smith AC and Maher ER: Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: Analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour. Br J Cancer. 92:1574–1580. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Gejman R, Batista DL, Zhong Y, Zhou Y, Zhang X, Swearingen B, Stratakis CA, Hedley-Whyte ET and Klibanski A: Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. J Clin Endocrinol Metab. 93:4119–4125. 2008. View Article : Google Scholar : PubMed/NCBI

14 

Zhou Y, Zhong Y, Wang Y, Zhang X, Batista DL, Gejman R, Ansell PJ, Zhao J, Weng C and Klibanski A: Activation of p53 by MEG3 non-coding RNA. J Biol Chem. 282:24731–24742. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Sheng X and Li J, Yang L, Chen Z, Zhao Q, Tan L, Zhou Y and Li J: Promoter hypermethylation influences the suppressive role of maternally expressed 3, a long non-coding RNA, in the development of epithelial ovarian cancer. Oncol Rep. 32:277–285. 2014.PubMed/NCBI

16 

Hervouet E, Vallette FM and Cartron PF: Impact of the DNA methyltransferases expression on the methylation status of apoptosis-associated genes in glioblastoma multiforme. Cell Death Dis. 1:e82010. View Article : Google Scholar : PubMed/NCBI

17 

Braconi C, Kogure T, Valeri N, Huang N, Nuovo G, Costinean S, Negrini M, Miotto E, Croce CM and Patel T: microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene. 30:4750–4756. 2011. View Article : Google Scholar : PubMed/NCBI

18 

Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, Hahn WC, Ligon KL, Louis DN, Brennan C, et al: Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 21:2683–2710. 2007. View Article : Google Scholar : PubMed/NCBI

19 

Zhou Y, Zhang X and Klibanski A: MEG3 noncoding RNA: A tumor suppressor. J Mol Endocrinol. 48:R45–R53. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Yan J, Guo X, Xia J, Shan T, Gu C, Liang Z, Zhao W and Jin S: MiR-148a regulates MEG3 in gastric cancer by targeting DNA methyltransferase 1. Med Oncol. 31:8792014. View Article : Google Scholar : PubMed/NCBI

21 

Zhang X, Gejman R, Mahta A, Zhong Y, Rice KA, Zhou Y, Cheunsuchon P, Louis DN and Klibanski A: Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res. 70:2350–2358. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Zhao J, Dahle D, Zhou Y, Zhang X and Klibanski A: Hyper-methylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. J Clin Endocrinol Metab. 90:2179–2186. 2005. View Article : Google Scholar : PubMed/NCBI

23 

Kuo HK, Griffith JD and Kreuzer KN: 5-Azacytidine induced methyltransferase-DNA adducts block DNA replication in vivo. Cancer Res. 67:8248–8254. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Lengauer C, Kinzler KW and Vogelstein B: DNA methylation and genetic instability in colorectal cancer cells. Proc Natl Acad Sci USA. 94:2545–2550. 1997. View Article : Google Scholar : PubMed/NCBI

25 

Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, et al: Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell. 21:430–446. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Wang P, Ren Z and Sun P: Overexpression of the long non-coding RNA MEG3 impairs in vitro glioma cell proliferation. J Cell Biochem. 113:1868–1874. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Jurkowska RZ, Jurkowski TP and Jeltsch A: Structure and function of mammalian DNA methyltransferases. ChemBioChem. 12:206–222. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Kreth S, Thon N, Eigenbrod S, Lutz J, Ledderose C, Egensperger R, Tonn JC, Kretzschmar HA, Hinske LC and Kreth FW: O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation. PLoS One. 6:e171562011. View Article : Google Scholar : PubMed/NCBI

29 

Nakagawa T, Kanai Y, Ushijima S, Kitamura T, Kakizoe T and Hirohashi S: DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression during multistage urothelial carcinogenesis. J Urol. 173:1767–1771. 2005. View Article : Google Scholar : PubMed/NCBI

30 

Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H and Hirohashi S: Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer. 105:527–532. 2003. View Article : Google Scholar : PubMed/NCBI

31 

Bian EB, Zhao B, Huang C, Wang H, Meng XM, Wu BM, Ma TT, Zhang L, Lv XW and Li J: New advances of DNA methylation in liver fibrosis, with special emphasis on the crosstalk between microRNAs and DNA methylation machinery. Cell Signal. 25:1837–1844. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Foltz G, Yoon JG, Lee H, Ryken TC, Sibenaller Z, Ehrich M, Hood L and Madan A: DNA methyltransferase-mediated transcriptional silencing in malignant glioma: A combined whole-genome microarray and promoter array analysis. Oncogene. 28:2667–2677. 2009. View Article : Google Scholar : PubMed/NCBI

33 

Vogelstein B, Lane D and Levine AJ: Surfing the p53 network. Nature. 408:307–310. 2000. View Article : Google Scholar : PubMed/NCBI

34 

Lu KH, Li W, Liu XH, Sun M, Zhang ML, Wu WQ, Xie WP and Hou YY: Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer. 13:4612013. View Article : Google Scholar : PubMed/NCBI

35 

Zhang X, Rice K, Wang Y, Chen W, Zhong Y, Nakayama Y, Zhou Y and Klibanski A: Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: Isoform structure, expression, and functions. Endocrinology. 151:939–947. 2010. View Article : Google Scholar :

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Copy and paste a formatted citation
APA
Li, J., Bian, E., He, X., Ma, C., Zong, G., Wang, H., & Zhao, B. (2016). Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas. International Journal of Oncology, 48, 723-733. https://doi.org/10.3892/ijo.2015.3285
MLA
Li, J., Bian, E., He, X., Ma, C., Zong, G., Wang, H., Zhao, B."Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas". International Journal of Oncology 48.2 (2016): 723-733.
Chicago
Li, J., Bian, E., He, X., Ma, C., Zong, G., Wang, H., Zhao, B."Epigenetic repression of long non-coding RNA MEG3 mediated by DNMT1 represses the p53 pathway in gliomas". International Journal of Oncology 48, no. 2 (2016): 723-733. https://doi.org/10.3892/ijo.2015.3285