Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Research Article

Dextran Sulfate Inhibits Cell Proliferation and Induces Apoptosis by Regulating EZH2 in Gastric Carcinoma

Author(s): Yunning Huang *, Wenjun Wang*, Yuan-Yi Xu*, Jiaxin Guo, Longxing Jiao, Honghong Wang, Mengqi Li and Qi Yang

Volume 21, Issue 11, 2021

Published on: 22 September, 2021

Page: [953 - 964] Pages: 12

DOI: 10.2174/1568009621666210922112039

Price: $65

Abstract

Background: Gastric cancer (GC) is one of the most common gastrointestinal malignancies. According to reports, the enhancer of zeste homolog 2 (EZH2) exhibits carcinogenic function in a variety of cancers. Therefore, EZH2 may be a potential therapeutic target for the treatment of human cancer. Macromolecular Dextran Sulfate (DS) has been displayed to play a critical role in tumor inhibition. However, the molecular mechanism by which DS mediates this effect is unclear.

Objectives: In this study, we explored the effects of DS on the proliferation and apoptosis of gastric cancer and the related mechanisms. Cell proliferation and counting assays, as well as cell colony formation assays, revealed that DS inhibited the proliferation and tumorigenesis of GC cells. Additionally, flow cytometry analysis displayed that DS blocked the cell cycle of GC cells in the G1/S phase and promoted their apoptosis.

Methods: Bioinformatics analyses, enzyme-linked immunosorbent assays, immunohistochemistry, and other methods were applied to measure the expression of EZH2 in human GC cells and tissues.

Results and Discussion: Further studies have shown that DS treatment can reduce the expression of proliferating cell nuclear antigen (PCNA) and increase the level of the ratio of Bax: Bcl-2 protein in GC cells. In addition, DS reduced EZH2 levels and increased CXXC finger protein 4 levels both in vitro and in vivo. In addition, down-regulation of EZH2 with EZH2 inhibitors reversed the inhibitory effect of DS on gastric cancer cells.

Conclusion: Collectively, our work demonstrates that DS suppresses proliferation and promotes apoptosis of GC cells by regulating EZH2. Our study suggests that DS is a promising therapeutic compound for the treatment of GC.

Keywords: Dextran sulfate, gastric cancer, EZH2, CXXC4, proliferation, apoptosis.

« Previous Next »
Graphical Abstract

[1]
Huang, K.K.; Ramnarayanan, K.; Zhu, F.; Srivastava, S.; Xu, C.; Tan, A.L.K.; Lee, M.; Tay, S.; Das, K.; Xing, M.; Fatehullah, A.; Alkaff, S.M.F.; Lim, T.K.H.; Lee, J.; Ho, K.Y.; Rozen, S.G.; Teh, B.T.; Barker, N.; Chia, C.K.; Khor, C.; Ooi, C.J.; Fock, K.M.; So, J.; Lim, W.C.; Ling, K.L.; Ang, T.L.; Wong, A.; Rao, J.; Rajnakova, A.; Lim, L.G.; Yap, W.M.; Teh, M.; Yeoh, K.G.; Tan, P. Genomic and epigenomic profiling of high-risk intestinal metaplasia reveals molecular determinants of progression to gastric cancer. Cancer Cell, 2018, 33(1), 137-150.e5.
[http://dx.doi.org/10.1016/j.ccell.2017.11.018] [PMID: 29290541]
[2]
Rugge, M.; Genta, R.M.; Di Mario, F.; El-Omar, E.M.; El-Serag, H.B.; Fassan, M.; Hunt, R.H.; Kuipers, E.J.; Malfertheiner, P.; Sugano, K.; Graham, D.Y. Gastric cancer as preventable disease. Clin. Gastroenterol. Hepatol., 2017, 15(12), 1833-1843.
[http://dx.doi.org/10.1016/j.cgh.2017.05.023] [PMID: 28532700]
[3]
Hagiwara, A.; Sawai, K.; Sakakura, C.; Shirasu, M.; Ohgaki, M.; Imanishi, T.; Yamasaki, J.; Togawa, T.; Takahashi, T. Prevention of peritoneal metastasis of cancer with dextran sulfate- an experimental study in mice. Anticancer Drugs, 1997, 8(9), 894-897.
[http://dx.doi.org/10.1097/00001813-199710000-00011] [PMID: 9402317]
[4]
Xu, Y.; Jin, X.; Huang, Y.; Wang, J.; Wang, X.; Wang, H. Dextran sulfate inhibition on human gastric cancer cells invasion, migration and epithelial-mesenchymal transformation. Oncol. Lett., 2018, 16(4), 5041-5049.
[http://dx.doi.org/10.3892/ol.2018.9251] [PMID: 30250571]
[5]
Xu, Y.; Wang, X.; Huang, Y.; Ma, Y.; Jin, X.; Wang, H.; Wang, J. Inhibition of lysyl oxidase expression by dextran sulfate affects invasion and migration of gastric cancer cells. Int. J. Mol. Med., 2018, 42(5), 2737-2749.
[PMID: 30226558]
[6]
Sparmann, A.; van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer, 2006, 6(11), 846-856.
[http://dx.doi.org/10.1038/nrc1991] [PMID: 17060944]
[7]
Jung, H.Y.; Jun, S.; Lee, M.; Kim, H.C.; Wang, X.; Ji, H.; McCrea, P.D.; Park, J.I. PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation. Mol. Cell, 2013, 52(2), 193-205.
[http://dx.doi.org/10.1016/j.molcel.2013.08.028] [PMID: 24055345]
[8]
Bachmann, I.M.; Halvorsen, O.J.; Collett, K.; Stefansson, I.M.; Straume, O.; Haukaas, S.A.; Salvesen, H.B.; Otte, A.P.; Akslen, L.A. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J. Clin. Oncol., 2006, 24(2), 268-273.
[http://dx.doi.org/10.1200/JCO.2005.01.5180] [PMID: 16330673]
[9]
Yuan, J.B.; Yang, L.Y.; Tang, Z.Y.; Zu, X.B.; Qi, L. Down-regulation of EZH2 by RNA interference inhibits proliferation and invasion of ACHN cells via the Wnt/β- catenin pathway. Asian Pac. J. Cancer Prev., 2012, 13(12), 6197-6201.
[http://dx.doi.org/10.7314/APJCP.2012.13.12.6197] [PMID: 23464430]
[10]
Arai, Y.; Honda, S.; Haruta, M.; Kasai, F.; Fujiwara, Y.; Ohshima, J.; Sasaki, F.; Nakagawara, A.; Horie, H.; Yamaoka, H.; Hiyama, E.; Kaneko, Y. Genome-wide analysis of allelic imbalances reveals 4q deletions as a poor prognostic factor and MDM4 amplification at 1q32.1 in hepatoblastoma. Genes Chromosomes Cancer, 2010, 49(7), 596-609.
[PMID: 20461752]
[11]
Brosens, R.P.; Belt, E.J.; Haan, J.C.; Buffart, T.E.; Carvalho, B.; Grabsch, H.; Quirke, P.; Cuesta, M.A.; Engel, A.F.; Ylstra, B.; Meijer, G.A. Deletion of chromosome 4q predicts outcome in stage II colon cancer patients. Cell Oncol. (Dordr.), 2011, 34(3), 215-223.
[http://dx.doi.org/10.1007/s13402-011-0042-8] [PMID: 21717218]
[12]
Kojima, T.; Shimazui, T.; Hinotsu, S.; Joraku, A.; Oikawa, T.; Kawai, K.; Horie, R.; Suzuki, H.; Nagashima, R.; Yoshikawa, K.; Michiue, T.; Asashima, M.; Akaza, H.; Uchida, K. Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling. Oncogene, 2009, 28(2), 297-305.
[http://dx.doi.org/10.1038/onc.2008.391] [PMID: 18931698]
[13]
Stewart, D.J.; Chang, D.W.; Ye, Y.; Spitz, M.; Lu, C.; Shu, X.; Wampfler, J.A.; Marks, R.S.; Garces, Y.I.; Yang, P.; Wu, X. Wnt signaling pathway pharmacogenetics in non-small cell lung cancer. Pharmacogenomics J., 2014, 14(6), 509-522.
[http://dx.doi.org/10.1038/tpj.2014.21] [PMID: 24980784]
[14]
Ko, M.; An, J.; Bandukwala, H.S.; Chavez, L.; Aijö, T.; Pastor, W.A.; Segal, M.F.; Li, H.; Koh, K.P.; Lähdesmäki, H.; Hogan, P.G.; Aravind, L.; Rao, A. Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature, 2013, 497(7447), 122-126.
[http://dx.doi.org/10.1038/nature12052] [PMID: 23563267]
[15]
Lu, H.; Sun, J.; Wang, F.; Feng, L.; Ma, Y.; Shen, Q.; Jiang, Z.; Sun, X.; Wang, X.; Jin, H. Enhancer of zeste homolog 2 activates wnt signaling through downregulating CXXC finger protein 4. Cell Death Dis., 2013, 4, e776.
[http://dx.doi.org/10.1038/cddis.2013.293] [PMID: 23949225]
[16]
Waddell, T.; Verheij, M.; Allum, W.; Cunningham, D.; Cervantes, A.; Arnold, D. Gastric cancer: ESMO-ESSO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Radiother. Oncol., 2014, 110(1), 189-194.
[http://dx.doi.org/10.1016/j.radonc.2013.09.015] [PMID: 24636158]
[17]
Li, T.; Fan, J.; Wang, B.; Traugh, N.; Chen, Q.; Liu, J.S.; Li, B.; Liu, X.S. Timer: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res., 2017, 77(21), e108-e110.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0307] [PMID: 29092952]
[18]
Li, B.; Severson, E.; Pignon, J.C.; Zhao, H.; Li, T.; Novak, J.; Jiang, P.; Shen, H.; Aster, J.C.; Rodig, S.; Signoretti, S.; Liu, J.S.; Liu, X.S. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol., 2016, 17(1), 174.
[http://dx.doi.org/10.1186/s13059-016-1028-7] [PMID: 27549193]
[19]
Tang, Z.; Kang, B.; Li, C.; Chen, T.; Zhang, Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res., 2019, 47(W1), W556-W560.
[http://dx.doi.org/10.1093/nar/gkz430] [PMID: 31114875]
[20]
Miranda, T.B.; Cortez, C.C.; Yoo, C.B.; Liang, G.; Abe, M.; Kelly, T.K.; Marquez, V.E.; Jones, P.A. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther., 2009, 8(6), 1579-1588.
[http://dx.doi.org/10.1158/1535-7163.MCT-09-0013] [PMID: 19509260]
[21]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[22]
Kohi, S.; Sato, N.; Cheng, X.B.; Koga, A.; Hirata, K. Increased expression of HYAL1 in pancreatic ductal adenocarcinoma. Pancreas, 2016, 45(10), 1467-1473.
[http://dx.doi.org/10.1097/MPA.0000000000000670] [PMID: 27622341]
[23]
Wu, M.; Cao, M.; He, Y.; Liu, Y.; Yang, C.; Du, Y.; Wang, W.; Gao, F. A novel role of low molecular weight hyaluronan in breast cancer metastasis. FASEB J., 2015, 29(4), 1290-1298.
[http://dx.doi.org/10.1096/fj.14-259978] [PMID: 25550464]
[24]
Zhou, L.; Wei, E.; Zhou, B.; Bi, G.; Gao, L.; Zhang, T.; Huang, J.; Wei, Y.; Ge, B. Anti-proliferative benefit of curcumol on human bladder cancer cells via inactivating EZH2 effector. Biomed. Pharmacother., 2018, 104, 798-805.
[http://dx.doi.org/10.1016/j.biopha.2018.05.101] [PMID: 29852354]
[25]
Chen, Z.; Yang, P.; Li, W.; He, F.; Wei, J.; Zhang, T.; Zhong, J.; Chen, H.; Cao, J. Expression of EZH2 is associated with poor outcome in colorectal cancer. Oncol. Lett., 2018, 15(3), 2953-2961.
[PMID: 29435024]
[26]
Jones, B.A.; Varambally, S.; Arend, R.C. Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer. Mol. Cancer Ther., 2018, 17(3), 591-602.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0437] [PMID: 29726819]
[27]
Lu, F.; Xu, H.; Wang, Q.; Li, M.; Meng, J.; Kuang, Y. Inhibition of enhancer of zeste homolog 2 increases the expression of p16 and suppresses the proliferation and migration of ovarian carcinoma cells in vitro and in vivo. Oncol. Lett., 2018, 15(3), 3233-3239.
[PMID: 29435063]
[28]
Zhang, L.; Fang, F.; He, X. Long noncoding RNA TP73-AS1 promotes non-small cell lung cancer progression by competitively sponging miR-449a/EZH2. Biomed. Pharmacother., 2018, 104, 705-711.
[http://dx.doi.org/10.1016/j.biopha.2018.05.089] [PMID: 29803931]
[29]
Chien, Y.C.; Liu, L.C.; Ye, H.Y.; Wu, J.Y.; Yu, Y.L. EZH2 promotes migration and invasion of triple-negative breast cancer cells via regulating TIMP2-MMP-2/-9 pathway. Am. J. Cancer Res., 2018, 8(3), 422-434.
[PMID: 29636998]
[30]
Yin, Y.; Qiu, S.; Li, X.; Huang, B.; Xu, Y.; Peng, Y. EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. J. Neuroinflammation, 2017, 14(1), 220.
[http://dx.doi.org/10.1186/s12974-017-0993-4] [PMID: 29132376]
[31]
Zhang, J.; Chen, L.; Han, L.; Shi, Z.; Zhang, J.; Pu, P.; Kang, C. EZH2 is a negative prognostic factor and exhibits pro-oncogenic activity in glioblastoma. Cancer Lett., 2015, 356(2 Pt B), 929-936.
[http://dx.doi.org/10.1016/j.canlet.2014.11.003] [PMID: 25444902]
[32]
Han, M.; Dai, D.; Yousafzai, N.A.; Wang, F.; Wang, H.; Zhou, Q.; Lu, H.; Xu, W.; Feng, L.; Jin, H.; Wang, X. CXXC4 activates apoptosis through up-regulating GDF15 in gastric cancer. Oncotarget, 2017, 8(61), 103557-103567.
[http://dx.doi.org/10.18632/oncotarget.21581] [PMID: 29262584]
[33]
Chen, L.; Wu, Y.; Wu, Y.; Wang, Y.; Sun, L.; Li, F. The inhibition of EZH2 ameliorates osteoarthritis development through the Wnt/β-catenin pathway. Sci. Rep., 2016, 6, 29176.
[http://dx.doi.org/10.1038/srep29176] [PMID: 27539752]
[34]
Chen, Q.; Zheng, P.S.; Yang, W.T. EZH2-mediated repression of GSK-3β and TP53 promotes Wnt/β-catenin signaling-dependent cell expansion in cervical carcinoma. Oncotarget, 2016, 7(24), 36115-36129.
[http://dx.doi.org/10.18632/oncotarget.8741] [PMID: 27092879]
[35]
Moon, R.T.; Kohn, A.D.; De Ferrari, G.V.; Kaykas, A. WNT and beta-catenin signalling: diseases and therapies. Nat. Rev. Genet., 2004, 5(9), 691-701.
[http://dx.doi.org/10.1038/nrg1427] [PMID: 15372092]
[36]
Barker, N.; Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nat. Rev. Drug Discov., 2006, 5(12), 997-1014.
[http://dx.doi.org/10.1038/nrd2154] [PMID: 17139285]
[37]
Dihlmann, S.; von Knebel Doeberitz, M. Wnt/beta-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int. J. Cancer, 2005, 113(4), 515-524.
[http://dx.doi.org/10.1002/ijc.20609] [PMID: 15472907]
[38]
Cheng, A.S.; Lau, S.S.; Chen, Y.; Kondo, Y.; Li, M.S.; Feng, H.; Ching, A.K.; Cheung, K.F.; Wong, H.K.; Tong, J.H.; Jin, H.; Choy, K.W.; Yu, J.; To, K.F.; Wong, N.; Huang, T.H.; Sung, J.J. EZH2-mediated concordant repression of Wnt antagonists promotes β-catenin-dependent hepatocarcinogenesis. Cancer Res., 2011, 71(11), 4028-4039.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-3342] [PMID: 21512140]

Rights & Permissions Print Cite
Article Metrics
14
2
© 2024 Bentham Science Publishers | Privacy Policy