NFAT1 Hypermethylation Promotes Epithelial-Mesenchymal Transition and Metastasis in Nasopharyngeal Carcinoma by Activating ITGA6 Transcription

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2019 Feb 18

PMID 30772768

Citations 4

Authors

Jian Zhang

Zi-Qi Zheng

Ya-Wei Yuan

Pan-Pan Zhang

Ying-Qin Li

Ya-Qin Wang

Xin-Ran Tang

Xin Wen

Xiao-Hong Hong

Yuan Lei

Qing-Mei He

Xiao-Jing Yang

Ying Sun

Jun Ma

Na Liu

Affiliations

Soon will be listed here.

Abstract

DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.

Citing Articles

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Regulation and Functions of α6-Integrin (CD49f) in Cancer Biology.

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Zhang J, Jiang H, Xie T, Zheng J, Tian Y, Li R Front Genet. 2020; 11:52.

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References

Mane S, Thoh M, Sharma D, Sandur S, Naidu K . Ascorbyl Stearate Promotes Apoptosis Through Intrinsic Mitochondrial Pathway in HeLa Cancer Cells. Anticancer Res. 2016; 36(12):6409-6417. DOI: 10.21873/anticanres.11238. View

Shoshan E, Braeuer R, Kamiya T, Mobley A, Huang L, Vasquez M . NFAT1 Directly Regulates IL8 and MMP3 to Promote Melanoma Tumor Growth and Metastasis. Cancer Res. 2016; 76(11):3145-55. PMC: 4891299. DOI: 10.1158/0008-5472.CAN-15-2511. View

Gan L, Meng J, Xu M, Liu M, Qi Y, Tan C . Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer. Oncogene. 2017; 37(6):744-755. DOI: 10.1038/onc.2017.363. View

Zhang J, Wen X, Liu N, Li Y, Tang X, Wang Y . Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest. J Exp Clin Cancer Res. 2017; 36(1):147. PMC: 5649082. DOI: 10.1186/s13046-017-0621-2. View

Irnaten M, Zhdanov A, Brennan D, Crotty T, Clark A, Papkovsky D . Activation of the NFAT-Calcium Signaling Pathway in Human Lamina Cribrosa Cells in Glaucoma. Invest Ophthalmol Vis Sci. 2018; 59(2):831-842. DOI: 10.1167/iovs.17-22531. View

Jain J, Burgeon E, Badalian T, Hogan P, Rao A . A similar DNA-binding motif in NFAT family proteins and the Rel homology region. J Biol Chem. 1995; 270(8):4138-45. View

Cao S, Simons M, Qian C . The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer. 2011; 30(2):114-9. PMC: 4013340. DOI: 10.5732/cjc.010.10377. View

Zhao X, Wang Q, Yang S, Chen C, Li X, Liu J . Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer. Eur J Pharmacol. 2016; 781:60-8. DOI: 10.1016/j.ejphar.2016.03.063. View

Zhang J, Tian X, Xing J . Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J Clin Med. 2016; 5(4). PMC: 4850464. DOI: 10.3390/jcm5040041. View

10.

Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y . Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene. 2015; 34(49):5960-70. PMC: 4672172. DOI: 10.1038/onc.2015.46. View

11.

Jiang D, Shen Y, Dai D, Xu Y, Xu C, Zhu H . Meta-analyses of methylation markers for prostate cancer. Tumour Biol. 2014; 35(10):10449-55. DOI: 10.1007/s13277-014-2300-7. View

12.

Shakeri H, Fakhrjou A, Nikanfar A, Mohaddes-Ardebili S . Methylation Analysis of BRCA1 and APC in Breast Cancer and It's Relationship to Clinicopathological Features. Clin Lab. 2017; 62(12):2333-2337. DOI: 10.7754/Clin.Lab.2016.160418. View

13.

Zhang K, Myllymaki S, Gao P, Devarajan R, Kytola V, Nykter M . Oncogenic K-Ras upregulates ITGA6 expression via FOSL1 to induce anoikis resistance and synergizes with αV-Class integrins to promote EMT. Oncogene. 2017; 36(41):5681-5694. PMC: 5658677. DOI: 10.1038/onc.2017.177. View

14.

Dai W, Cheung A, Ko J, Cheng Y, Zheng H, Ngan R . Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma. Cancer Med. 2015; 4(7):1079-90. PMC: 4529346. DOI: 10.1002/cam4.451. View

15.

Yoeli-Lerner M, Chin Y, Hansen C, Toker A . Akt/protein kinase b and glycogen synthase kinase-3beta signaling pathway regulates cell migration through the NFAT1 transcription factor. Mol Cancer Res. 2009; 7(3):425-32. PMC: 2667900. DOI: 10.1158/1541-7786.MCR-08-0342. View

16.

Yiu G, Toker A . NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem. 2006; 281(18):12210-7. DOI: 10.1074/jbc.M600184200. View

17.

Ram B, Dolpady J, Kulkarni R, Usha R, Bhoria U, Poli U . Human papillomavirus (HPV) oncoprotein E6 facilitates Calcineurin-Nuclear factor for activated T cells 2 (NFAT2) signaling to promote cellular proliferation in cervical cell carcinoma. Exp Cell Res. 2017; 362(1):132-141. DOI: 10.1016/j.yexcr.2017.11.010. View

18.

Wang N, Sui F, Ma J, Su X, Liu J, Yao D . Site-specific Hypermethylation of RUNX3 Predicts Poor Prognosis in Gastric Cancer. Arch Med Res. 2016; 47(4):285-92. DOI: 10.1016/j.arcmed.2016.07.011. View

19.

Robbs B, Cruz A, Werneck M, Mognol G, Viola J . Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol. 2008; 28(23):7168-81. PMC: 2593389. DOI: 10.1128/MCB.00256-08. View

20.

Viola J, Carvalho L, Fonseca B, Teixeira L . NFAT transcription factors: from cell cycle to tumor development. Braz J Med Biol Res. 2005; 38(3):335-44. DOI: 10.1590/s0100-879x2005000300003. View