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Cancer Cell International
Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Primary research

TET2 suppresses nasopharyngeal carcinoma progression by inhibiting glycolysis metabolism

Authors: Xixia Zhang, Jing Yang, Dong Shi, Zhiwei Cao

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Nasopharyngeal carcinoma (NPC) is a common malignant tumor. Ten-eleven translocation (TET) protein 2 (TET2), an evolutionarily conserved dioxygenases, is reported to be involved in various malignant tumor developments. Here, we aim to investigate the effect of TET2 on NPC progress in vitro and in vivo, and its detailed underlying mechanism.

Methods

Real-time PCR and western blotting were used to determine the expression levels of TET1/2/3 in NPC cell lines. The effects of TET2 on NPC progression were evaluated using CCK8 and invasion assays in vitro. Proteins interacted with TET2 in NPC cells were detected by immunoprecipitation and mass spectrometry. The effects of TET2 or pyruvate kinase, muscle (PKM) on glycolysis in NPC cells were examined by detecting glucose uptake and lactate production. The effects of TET2 on NPC progression were evaluated using xenograft tumor model in vivo.

Results

TET2 expression was decreased in NPC cells, and TET2 overexpression inhibited proliferation and invasion of NPC cells, which is independent on TET2’s catalytic activity. In mechanism, TET2 N-terminal domain interacts with PKM in cytoplasm to prevent PKM dimers from translocating into nucleus, suppressing glycolysis in NPC cells, thereby inhibiting proliferation and invasion of NPC cells. Moreover, using xenograft tumor model, we found that TET2 knockout promoted NPC progression and decreased survival rate. However, administration with the inhibitor of PKM, shikonin, decreased the tumor volume of TET2-cas9 group, and increased the survival rate.

Conclusion

TET2 suppresses NPC development through interacting with PKM to inhibit glycolysis.
Appendix
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Literature
1.
Blanchard P, Nguyen F, Moya-Plana A, Pignon JP, Even C, Bidault F, Temam S, Ruffier A, Tao Y. New developments in the management of nasopharyngeal carcinoma. Cancer Radiother. 2018;22:492–5.PubMedCrossRef
2.
Hong M, Tang K, Qian J, Deng H, Zeng M, Zheng S, Ding K, Du Y, Sun R. Immunotherapy for EBV-Associated nasopharyngeal carcinoma. Crit Rev Oncog. 2018;23:219–34.PubMedCrossRef
3.
Lu T, Chen Y, Li J, Guo Q, Lin W, Zheng Y, Su Y, Zong J, Lin S, Ye Y, Pan J. High soluble programmed death-ligand 1 predicts poor prognosis in patients with nasopharyngeal carcinoma. OncoTargets Ther. 2020;13:1757–65.CrossRef
4.
5.
Wang F, Zhang J, Qi J. Ten-eleven translocation-2 affects the fate of cells and has therapeutic potential in digestive tumors. Chronic Dis Transl Med. 2019;5:267–72.PubMed
6.
Chapel DB, Husain AN, Krausz T. Immunohistochemical evaluation of nuclear 5-hydroxymethylcytosine (5-hmC) accurately distinguishes malignant pleural mesothelioma from benign mesothelial proliferations. Mod Pathol. 2019;32(3):376–86.PubMedCrossRef
7.
Santiago M, Antunes C, Guedes M, Sousa N, Marques CJ. TET enzymes and DNA hydroxymethylation in neural development and function–how critical are they? Genomics. 2014;104:334–40.PubMedCrossRef
8.
Pellissery S, Richter J, Haake A, Montesinos-Rongen M, Deckert M, Siebert R. Somatic mutations altering Tyr641 of EZH2 are rare in primary central nervous system lymphoma. Leukemia Lymphoma. 2010;51:2135–6.PubMedCrossRef
9.
Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42:181–5.PubMedPubMedCentralCrossRef
10.
Lessard J, Schumacher A, Thorsteinsdottir U, van Lohuizen M, Magnuson T, Sauvageau G. Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation. Genes Dev. 1999;13:2691–703.PubMedPubMedCentralCrossRef
11.
Pan W, Zhu S, Qu K, Meeth K, Cheng J, He K, Ma H, Liao Y, Wen X, Roden C, Tobiasova Z. The DNA methylcytosine dioxygenase Tet2 sustains immunosuppressive function of tumor-infiltrating myeloid cells to promote melanoma progression. Immunity. 2017;47(2):284–97.PubMedPubMedCentralCrossRef
12.
Zhou K, Guo H, Zhang J, Zhao D, Zhou Y, Zheng Z, Xu Y, Li Y, Wang D. Potential role of TET2 in gastric cancer cisplatin resistance. Pathol Res Pract. 2019;215:152637.PubMedCrossRef
13.
14.
Jia J, Shi Y, Chen L, Lai W, Yan B, Jiang Y, Xiao D, Xi S, Cao Y, Liu S, Cheng Y, Tao Y. Decrease in lymphoid specific helicase and 5-hydroxymethylcytosine is associated with metastasis and genome instability. Theranostics. 2017;7:3920–32.PubMedPubMedCentralCrossRef
15.
Sung WW, Chen PR, Liao MH, Lee JW. Enhanced aerobic glycolysis of nasopharyngeal carcinoma cells by Epstein-Barr virus latent membrane protein 1. Exp Cell Res. 2017;359:94–100.PubMedCrossRef
16.
17.
Sheng H, Tang W. Glycolysis inhibitors for anticancer therapy: a review of recent patents, Recent patents on anti-cancer. Drug Discov. 2016;11(3):297–308.
18.
W.J. Israelsen, M.G. Vander Heiden, Pyruvate kinase: Function, regulation and role in cancer, Seminars in cell & developmental biology 43 (2015) 43-51.
19.
Li T, Han J, Jia L, Hu X, Chen L, Wang Y. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation. Protein Cell. 2019;10:583–94.PubMedPubMedCentralCrossRef
20.
Van Wilpe S, Koornstra R, Den Brok M, De Groot JW, Blank C, De Vries J, Gerritsen W, Mehra N. Lactate dehydrogenase: a marker of diminished antitumor immunity. Oncoimmunology. 2020;9:1731942.PubMedPubMedCentralCrossRef
21.
22.
Ning Z, Tan G. Cancer metabolism: a novel perspective on precision diagnosis and treatment for liver cancer. Zhonghua Wai Ke Za Zhi. 2020;58:31–6.PubMed
23.
Li X, Lu W, Hu Y, Wen S, Qian C, Wu W, Huang P. Effective inhibition of nasopharyngeal carcinoma in vitro and in vivo by targeting glycolysis with oxamate. Int J Oncol. 2013;43:1710–8.PubMedCrossRef
24.
Ye C, Tao R, Cao Q, Zhu D, Wang Y, Wang J, Lu J, Chen E, Li L. Whole-genome DNA methylation and hydroxymethylation profiling for HBV-related hepatocellular carcinoma. Int J Oncol. 2016;49:589–602.PubMedCrossRef
25.
Zhang X, Yang J, Bian Z, Shi D, Cao Z. Long noncoding RNA DANCR promotes nasopharyngeal carcinoma progression by interacting with STAT3, enhancing IL-6/JAK1/STAT3 signaling. Biomed Pharmacother. 2019;1(113):108713.CrossRef
26.
Ito K, Lee J, Chrysanthou S, Zhao Y, Josephs K, Sato H, Teruya-Feldstein J, Zheng D, Dawlaty MM, Ito K. Non-catalytic roles of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis. Cell Rep. 2019;28(10):2480–90.PubMedPubMedCentralCrossRef
27.
Zhang YW, Wang Z, Xie W, Cai Y, Xia L, Easwaran H, Luo J, Yen RC, Li Y, Baylin SB. Acetylation enhances TET2 function in protecting against abnormal DNA methylation during oxidative stress. Mol Cell. 2017;65:323–35.PubMedPubMedCentralCrossRef
28.
Yu S, Yin Y, Hong S, Cao S, Huang Y, Chen S, Liu Y, Guan H, Zhang Q, Li Y, Xiao H. TET1 is a tumor suppressor that inhibits papillary thyroid carcinoma cell migration and invasion. Int J Endocrinol. 2020;2020:3909610.PubMedPubMedCentral
29.
Carella A, Tejedor JR, Garcia MG, Urdinguio RG, Bayon GF, Sierra M, Lopez V, Garcia-Torano E, Santamarina-Ojeda P, Perez RF, Bigot T, Mangas C, Corte-Torres MD, Saenz-de-Santa-Maria I, Mollejo M, Melendez B, Astudillo A, Chiara MD, Fernandez AF, Fraga MF. Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis. Int J Cancer. 2020;146:373–87.PubMedCrossRef
30.
Chua GNL, Wassarman KL, Sun H, Alp JA, Jarczyk EI, Kuzio NJ, Bennett MJ, Malachowsky BG, Kruse M, Kennedy AJ. Cytosine-based TET enzyme inhibitors. ACS Med Chem Lett. 2019;10:180–5.PubMedPubMedCentralCrossRef
31.
Zhang D, An X, Li Z, Zhang S. Role of gene promoter methylation regulated by TETs and DNMTs in the overexpression of HLA-G in MCF-7 cells. Exp Ther Med. 2019;17:4709–14.PubMedPubMedCentral
32.
Zhang M, Zhang H, Hong H, Zhang Z. MiR-374b re-sensitizes hepatocellular carcinoma cells to sorafenib therapy by antagonizing PKM2-mediated glycolysis pathway. Am Journal Cancer Res. 2019;9:765–78.
33.
Xie R, Chen X, Chen Z, Huang M, Dong W, Gu P, Zhang J, Zhou Q, Dong W, Han J, Wang X, Li H, Huang J, Lin T. Polypyrimidine tract binding protein 1 promotes lymphatic metastasis and proliferation of bladder cancer via alternative splicing of MEIS2 and PKM. Cancer Lett. 2019;449:31–44.PubMedCrossRef
34.
Kong L, Tan L, Lv R, Shi Z, Xiong L, Wu F, Rabidou K, Smith M, He C, Zhang L, Qian Y, Ma D, Lan F, Shi Y, Shi YG. A primary role of TET proteins in establishment and maintenance of De Novo bivalency at CpG islands. Nucleic Acids Res. 2016;44:8682–92.PubMedPubMedCentralCrossRef
35.
Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, Schreiber SL, Mellor J, Kouzarides T. Active genes are tri-methylated at K4 of histone H3. Nature. 2002;419:407–11.PubMedCrossRef
36.
37.
Niller HH, Banati F, Salamon D, Minarovits J. Epigenetic alterations in Epstein-Barr virus-associated diseases. Adv Exp Med Biol. 2016;879:39–69.PubMedCrossRef
38.
Noguchi T, Inoue H, Tanaka T. The M1- and M2-type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem. 1986;261:13807–12.PubMedCrossRef
39.
Prakasam G, Singh RK, Iqbal MA, Saini SK, Tiku AB, Bamezai RNK. Pyruvate kinase M knockdown-induced signaling via AMP-activated protein kinase promotes mitochondrial biogenesis, autophagy, and cancer cell survival. J Biol Chem. 2017;292:15561–76.PubMedPubMedCentralCrossRef
40.
41.
Lee J, Kim HK, Han YM, Kim J. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription. Int J Biochem Cell Biol. 2008;40:1043–54.PubMedCrossRef
42.
Dasgupta B, Ju JS, Sasaki Y, Liu X, Jung SR, Higashida K, Lindquist D, Milbrandt J. The AMPK beta2 subunit is required for energy homeostasis during metabolic stress. Mol Cell Biol. 2012;32:2837–48.PubMedPubMedCentralCrossRef
43.
44.
Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov. 2016;6:353–67.PubMedCrossRef
45.
Liu Z, Cheng C, Luo X, Xia Q, Zhang Y, Long X, Jiang Q, Fang W. CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma. BMC Cancer. 2016;16:238.PubMedPubMedCentralCrossRef
46.
Jiang Q, Mai C, Yang H, Wu Q, Hua S, Yan C, Long Y, Zhang Y, Long X, Fang W, Liu Z. Nuclear expression of CDK4 correlates with disease progression and poor prognosis in human nasopharyngeal carcinoma. Histopathology. 2014;64:722–30.PubMedCrossRef
Metadata
Title
TET2 suppresses nasopharyngeal carcinoma progression by inhibiting glycolysis metabolism
Authors
Xixia Zhang
Jing Yang
Dong Shi
Zhiwei Cao
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01456-9

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