EZH2 Promotes Invasion and Tumour Glycolysis by Regulating STAT3 and FoxO1 Signalling in Human OSCC Cells

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2019 Aug 2

PMID 31368152

Citations 20

Authors

Min Zheng

Ming-Xin Cao

Xiao-Jie Luo

Li Li

Ke Wang

Sha-Sha Wang

Hao-Fan Wang

Ya-Jie Tang

Ya-Ling Tang

Xin-Hua Liang

Affiliations

Soon will be listed here.

Abstract

The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is an oncogene overexpressed in a variety of human cancers. Here, we found that EZH2 correlated with poor survival of oral squamous cell carcinoma (OSCC) patients using immunohistochemistry staining. EZH2 overexpression led to a significant induction in tumour glycolysis, Epithelial-mesenchymal transition (EMT), migration and invasion of OSCC cells. Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells. Ectopic overexpression of EZH2 increased phosphorylation of STAT3 at pY705 and decreased FoxO1 expression, and FoxO1 expression was enhanced when inhibiting STAT3. In addition, EZH2 overexpression led to a significant decrease in FoxO1 mRNA levels in nude mice xenograft. These results indicated that regulation of EZH2 might have the potential to be targeted for OSCC treatment.

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References

Zheng M, Cao M, Luo X, Li L, Wang K, Wang S . EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells. J Cell Mol Med. 2019; 23(10):6942-6954. PMC: 6787444. DOI: 10.1111/jcmm.14579. View

Kidani K, Osaki M, Tamura T, Yamaga K, Shomori K, Ryoke K . High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas. Oral Oncol. 2008; 45(1):39-46. DOI: 10.1016/j.oraloncology.2008.03.016. View

Geng J, Li X, Zhou Z, Wu C, Dai M, Bai X . EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer. Cancer Lett. 2015; 359(2):275-87. DOI: 10.1016/j.canlet.2015.01.031. View

Tao T, Chen M, Jiang R, Guan H, Huang Y, Su H . Involvement of EZH2 in aerobic glycolysis of prostate cancer through miR-181b/HK2 axis. Oncol Rep. 2017; 37(3):1430-1436. PMC: 5364858. DOI: 10.3892/or.2017.5430. View

Wang Y, Zhang X, Wang Z, Hu Q, Wu J, Li Y . LncRNA-p23154 promotes the invasion-metastasis potential of oral squamous cell carcinoma by regulating Glut1-mediated glycolysis. Cancer Lett. 2018; 434:172-183. DOI: 10.1016/j.canlet.2018.07.016. View

Vander Heiden M, Cantley L, Thompson C . Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009; 324(5930):1029-33. PMC: 2849637. DOI: 10.1126/science.1160809. View

Piao L, Sidhu V, Fang Y, Ryan J, Parikh K, Hong Z . FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4 (PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl). 2012; 91(3):333-46. PMC: 3584201. DOI: 10.1007/s00109-012-0982-0. View

Rao Z, Cai M, Yang G, He L, Mai S, Hua W . EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-beta1 and is a predictor of outcome in ovarian carcinoma patients. Carcinogenesis. 2010; 31(9):1576-83. DOI: 10.1093/carcin/bgq150. View

Ozes A, Pulliam N, Ertosun M, Yilmaz O, Tang J, Copuroglu E . Protein kinase A-mediated phosphorylation regulates STAT3 activation and oncogenic EZH2 activity. Oncogene. 2018; 37(26):3589-3600. PMC: 6023775. DOI: 10.1038/s41388-018-0218-z. View

10.

Zhang P, Song Y, Sun Y, Li X, Chen L, Yang L . AMPK/GSK3β/β-catenin cascade-triggered overexpression of CEMIP promotes migration and invasion in anoikis-resistant prostate cancer cells by enhancing metabolic reprogramming. FASEB J. 2018; 32(7):3924-3935. DOI: 10.1096/fj.201701078R. View

11.

Liu D, Sun L, Qin X, Liu T, Zhang S, Liu Y . HSF1 promotes the inhibition of EMT-associated migration by low glucose via directly regulating Snail1 expression in HCC cells. Discov Med. 2016; 22(120):87-96. View

12.

Xiong X, Tao R, DePinho R, Dong X . Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLoS One. 2013; 8(8):e74340. PMC: 3755981. DOI: 10.1371/journal.pone.0074340. View

13.

Wang Y, Guo W, Li Z, Wu Y, Jing C, Ren Y . Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion. Int J Oncol. 2018; 52(4):1149-1164. PMC: 5843395. DOI: 10.3892/ijo.2018.4293. View

14.

Ma W, Fuentes G, Shi X, Verma C, Radda G, Han W . FoxO1 negatively regulates leptin-induced POMC transcription through its direct interaction with STAT3. Biochem J. 2014; 466(2):291-8. DOI: 10.1042/BJ20141109. View

15.

Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L . Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol. 2015; 17(1):95-103. PMC: 4684796. DOI: 10.1038/ni.3313. View

16.

Aghazadeh S, Yazdanparast R . Mycophenolic acid potentiates HER2-overexpressing SKBR3 breast cancer cell line to induce apoptosis: involvement of AKT/FOXO1 and JAK2/STAT3 pathways. Apoptosis. 2016; 21(11):1302-1314. DOI: 10.1007/s10495-016-1288-4. View

17.

Pan Y, Wang C, Zhu M, Xing R, Cui J, Li W . STAT3 signaling drives EZH2 transcriptional activation and mediates poor prognosis in gastric cancer. Mol Cancer. 2016; 15(1):79. PMC: 5148878. DOI: 10.1186/s12943-016-0561-z. View

18.

Zhang X, Wu D, Aldarouish M, Yin X, Li C, Wang C . ETS-1: A potential target of glycolysis for metabolic therapy by regulating glucose metabolism in pancreatic cancer. Int J Oncol. 2016; 50(1):232-240. DOI: 10.3892/ijo.2016.3770. View

19.

Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H . EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget. 2016; 8(6):9557-9571. PMC: 5354753. DOI: 10.18632/oncotarget.13771. View

20.

Venkatesan N, Wong J, Tan K, Chung H, Yau Y, Cukuroglu E . EZH2 promotes neoplastic transformation through VAV interaction-dependent extranuclear mechanisms. Oncogene. 2017; 37(4):461-477. DOI: 10.1038/onc.2017.309. View