Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells

Cai,Kemin; Wan,Yi; Sun,Guan; Shi,Lei; Bao,Xueli; Wang,Zhimin

doi:10.3892/or.2012.2027

Let-7a inhibits proliferation and induces apoptosis by targeting EZH2 in nasopharyngeal carcinoma cells

Authors:
- Kemin Cai
- Yi Wan
- Guan Sun
- Lei Shi
- Xueli Bao
- Zhimin Wang
View Affiliations

Affiliations: Department of Otorhinolaryngology Head and Neck Surgery, Taizhou People's Hospital, Taizhou 225300, Jiangsu, P.R. China, Department of Neurosurgery, Suzhou Kowloon Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Suzhou 215021, P.R. China, Department of Neurosurgery, Fourth Affiliated Yancheng Hospital of Nantong University, Yancheng 224000, P.R. China, Department of Neurosurgery, The First People's Hospital of Kunshan affiliated with Jiangsu University, Suzhou 215300, P.R. China
Published online on: September 12, 2012 https://doi.org/10.3892/or.2012.2027
Pages: 2101-2106

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Let-7a is frequently downregulated in various types of human cancer including nasopharyngeal carcinoma. However, the underlying mechanism of let-7a action in nasopharyngeal carcinoma remains elusive. In this study, we show that the enhancer of zeste homolog 2 (EZH2) is a direct target of let-7a in human nasopharyngeal carcinoma cells. The inhibition of EZH2 in vitro by let-7a, EZH2 siRNA, attenuated nasopharyngeal carcinoma cell growth, inhibited cell proliferation and induced cell apoptosis. In addition, for each biological process we identified ontology-associated transcripts that significantly correlate with EZH2 expression. Finally, the expression of EZH2 significantly abrogated let-7a-mediated cell proliferation and apoptosis in the nasopharyngeal carcinoma cells. Taken together, our results suggest that let-7a and EZH2 may be potential therapeutic targets for nasopharyngeal carcinoma.

View Figures

View References

1	Shi L, Cheng Z, Zhang J, Li R, Zhao P, Fu Z and You Y: hsa-mir-181a and hsa-mir-181b function as tumor suppressors in human glioma cells. Brain Res. 1236:185–193. 2008. View Article : Google Scholar : PubMed/NCBI
2	Wang Y, Wang X, Zhang J, Sun G, Luo H, Kang C, Pu P, Jiang T, Liu N and You Y: MicroRNAs involved in the EGFR/PTEN/AKT pathway in gliomas. J Neurooncol. 106:217–224. 2012. View Article : Google Scholar : PubMed/NCBI
3	Liu N, Chen NY, Cui RX, Li WF, Li Y, Wei RR, Zhang MY, Sun Y, Huang BJ, Chen M, et al: Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. Lancet Oncol. 13:633–641. 2012. View Article : Google Scholar : PubMed/NCBI
4	Li T, Chen JX, Fu XP, Yang S, Zhang Z, Chen K-H and Li Y: microRNA expression profiling of nasopharyngeal carcinoma. Oncol Rep. 25:1353–1363. 2011.PubMed/NCBI
5	Chen SJ, Chen GH, Chen YH, Liu CY, Chang KP, Chang YS and Chen HC: Characterization of Epstein-Barr virus miRNAome in nasopharyngeal carcinoma by deep sequencing. PLoS One. 5:pii. e127452010. View Article : Google Scholar : PubMed/NCBI
6	Wong TS, Man OY, Tsang CM, Tsao SW, Tsang RK, Chan JY, Ho WK, Wei WI and To VS: MicroRNA let-7 suppresses nasopharyngeal carcinoma cells proliferation through downregulating c-Myc expression. J Cancer Res Clin Oncol. 137:415–422. 2011. View Article : Google Scholar : PubMed/NCBI
7	Carbon S, Ireland A, Mungall CJ, Shu S, Marshall B and Lewis S: AmiGO: online access to ontology and annotation data. Bioinformatics. 25:288–289. 2009. View Article : Google Scholar : PubMed/NCBI
8	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
9	Kim SJ, Shin JY, Lee KD, Bae YK, Sung KW, Nam SJ and Chun KH: MicroRNA let-7a suppresses breast cancer cell migration and invasion through downregulation of C-C chemokine receptor type 7. Breast Cancer Res. 14:R142012. View Article : Google Scholar : PubMed/NCBI
10	Liu Y, Yin B, Zhang C, Zhou L and Fan J: Hsa-let-7a functions as a tumor suppressor in renal cell carcinoma cell lines by targeting c-myc. Biochem Biophys Res Commun. 417:371–375. 2012. View Article : Google Scholar : PubMed/NCBI
11	Yang Q, Jie Z, Cao H, Greenlee AR, Yang C, Zou F and Jiang Y: Low-level expression of let-7a in gastric cancer and its involvement in tumorigenesis by targeting RAB40C. Carcinogenesis. 32:713–722. 2011. View Article : Google Scholar : PubMed/NCBI
12	Wang Y, Lu Y, Toh ST, Sung WK, Tan P, Chow P, Chung AY, Jooi LL and Lee CG: Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3. J Hepatol. 53:57–66. 2010. View Article : Google Scholar : PubMed/NCBI
13	Richly H, Aloia L and Di Croce L: Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis. 2:e2042011. View Article : Google Scholar : PubMed/NCBI
14	Margueron R and Reinberg D: The Polycomb complex PRC2 and its mark in life. Nature. 469:343–349. 2011. View Article : Google Scholar : PubMed/NCBI
15	Chang CJ and Hung MC: The role of EZH2 in tumour progression. Br J Cancer. 106:243–247. 2012. View Article : Google Scholar : PubMed/NCBI
16	Xiao Y: Enhancer of zeste homolog 2: a potential target for tumor therapy. Int J Biochem Cell Biol. 43:474–477. 2011. View Article : Google Scholar : PubMed/NCBI
17	Simon JA and Lange CA: Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res. 647:21–29. 2008. View Article : Google Scholar : PubMed/NCBI
18	Shin YJ and Kim JH: The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One. 7:e303932012. View Article : Google Scholar : PubMed/NCBI
19	Ntziachristos P, Tsirigos A, Van Vlierberghe P, Nedjic J, Trimarchi T, Flaherty MS, Ferres-Marco D, da Ros V, Tang Z, Siegle J, et al: Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med. 18:298–301. 2012. View Article : Google Scholar : PubMed/NCBI
20	Wang C, Liu Z, Woo CW, Li Z, Wang L, Wei JS, Marquez VE, Bates SE, Jin Q, Khan J, et al: EZH2 Mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3, and NGFR. Cancer Res. 72:315–324. 2012. View Article : Google Scholar : PubMed/NCBI
21	Huqun, Ishikawa R, Zhang J, Miyazawa H, Goto Y, Shimizu Y, Hagiwara K and Koyama N: Enhancer of zeste homolog 2 is a novel prognostic biomarker in nonsmall cell lung cancer. Cancer. 118:1599–1606. 2012. View Article : Google Scholar : PubMed/NCBI
22	Hwang CF, Huang HY, Chen CH, Chien CY, Hsu YC, Li CF and Fang FM: Enhancer of zeste homolog 2 overexpression in nasopharyngeal carcinoma: an independent poor prognosticator that enhances cell growth. Int J Radiat Oncol Biol Phys. 82:597–604. 2012. View Article : Google Scholar : PubMed/NCBI
23	Tong ZT, Cai MY, Wang XG, Kong LL, Mai SJ, Liu YH, Zhang HB, Liao YJ, Zheng F, Zhu W, et al: EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin. Oncogene. 31:583–594. 2012.PubMed/NCBI
24	Zheng F, Liao YJ, Cai MY, Liu YH, Liu TH, Chen SP, Bian XW, Guan XY, Lin MC, Zeng YX, et al: The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 61:278–289. 2012. View Article : Google Scholar : PubMed/NCBI
25	Liu X, Wang C, Chen Z, Jin Y, Wang Y, Kolokythas A, Dai Y and Zhou X: MicroRNA-138 suppresses epithelial-mesenchymal transition in squamous cell carcinoma cell lines. Biochem J. 440:23–31. 2011. View Article : Google Scholar : PubMed/NCBI
26	Juan AH, Kumar RM, Marx JG, Young RA and Sartorelli V: Mir-214-dependent regulation of the polycomb protein Ezh2 in skeletal muscle and embryonic stem cells. Mol Cell. 36:61–74. 2009. View Article : Google Scholar : PubMed/NCBI
27	Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q, Chen YC, Peng Y, Yao KT, Kung HF and Li XP: MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res. 71:225–233. 2011. View Article : Google Scholar : PubMed/NCBI
28	Alajez NM, Shi W, Hui AB, Bruce J, Lenarduzzi M, Ito E, Yue S, O’Sullivan B and Liu FF: Enhancer of Zeste homolog 2 (EZH2) is overexpressed in recurrent nasopharyngeal carcinoma and is regulated by miR-26a, miR-101, and miR-98. Cell Death Dis. 1:e852010. View Article : Google Scholar : PubMed/NCBI