Identification of EZH2 As Cancer Stem Cell Marker in Clear Cell Renal Cell Carcinoma and the Anti-Tumor Effect of Epigallocatechin-3-Gallate (EGCG)

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Sep 9

PMID 36077742

Authors

Chen Lyu

Lili Wang

Birgit Stadlbauer

Elfriede Noessner

Alexander Buchner

Heike Pohla

Affiliations

Soon will be listed here.

Abstract

The aim of the study was to develop a new therapeutic strategy to target cancer stem cells (CSCs) in clear cell renal cell carcinoma (ccRCC) and to identify typical CSC markers to improve therapy effectiveness. It was found that the corrected-mRNA expression-based stemness index was upregulated in kidney renal clear cell carcinoma (KIRC) tissues compared to non-tumor tissue and increased with higher tumor stage and grade. EZH2 was identified as a CSC marker and prognosis factor for KIRC patients. The expression of EZH2 was associated with several activated tumor-infiltrating immune cells. High expression of EZH2 was enriched in immune-related pathways, low expression was related to several metabolic pathways. Epigallocatechin-3-gallate (EGCG) was identified as the most potent suppressor of EZH2, was able to inhibit viability, migration, and invasion, and to increase the apoptosis rate of ccRCC CSCs. KIF11, VEGF, and MMP2 were identified as predictive EGCG target genes, suggesting a potential mechanism of how EZH2 might regulate invasiveness and migration. The percentages of FoxP3+ Treg cells in the peripheral blood mononuclear cells of ccRCC patients decreased significantly when cultured with spheres pretreated with EGCG plus sunitinib compared to spheres without treatment. Our findings provide new insights into the treatment options of ccRCC based on targeting CSCs.

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References

Straining R, Eighmy W . Tazemetostat: EZH2 Inhibitor. J Adv Pract Oncol. 2022; 13(2):158-163. PMC: 8955562. DOI: 10.6004/jadpro.2022.13.2.7. View

Koh W, Abu-Rustum N, Bean S, Bradley K, Campos S, Cho K . Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019; 17(1):64-84. DOI: 10.6004/jnccn.2019.0001. View

Bromwich E, McArdle P, Canna K, McMillan D, McNicol A, Brown M . The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer. Br J Cancer. 2003; 89(10):1906-8. PMC: 2394435. DOI: 10.1038/sj.bjc.6601400. View

Gassenmaier M, Chen D, Buchner A, Henkel L, Schiemann M, Mack B . CXC chemokine receptor 4 is essential for maintenance of renal cell carcinoma-initiating cells and predicts metastasis. Stem Cells. 2013; 31(8):1467-76. DOI: 10.1002/stem.1407. View

Adelaiye-Ogala R, Budka J, Damayanti N, Arrington J, Ferris M, Hsu C . EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming. Cancer Res. 2017; 77(23):6651-6666. PMC: 5712262. DOI: 10.1158/0008-5472.CAN-17-0899. View

Namiki K, Wongsirisin P, Yokoyama S, Sato M, Rawangkan A, Sakai R . (-)-Epigallocatechin gallate inhibits stemness and tumourigenicity stimulated by AXL receptor tyrosine kinase in human lung cancer cells. Sci Rep. 2020; 10(1):2444. PMC: 7016176. DOI: 10.1038/s41598-020-59281-z. View

Yuan Z, Mo J, Zhao G, Shu G, Fu H, Zhao W . Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells. Front Pharmacol. 2016; 7:423. PMC: 5103413. DOI: 10.3389/fphar.2016.00423. View

Zhou Q, Li K, Chen X, He H, Peng S, Peng S . HHLA2 and PD-L1 co-expression predicts poor prognosis in patients with clear cell renal cell carcinoma. J Immunother Cancer. 2020; 8(1). PMC: 7057441. DOI: 10.1136/jitc-2019-000157. View

Kempf J, Weser S, Bartoschek M, Metzeler K, Vick B, Herold T . Loss-of-function mutations in the histone methyltransferase EZH2 promote chemotherapy resistance in AML. Sci Rep. 2021; 11(1):5838. PMC: 7955088. DOI: 10.1038/s41598-021-84708-6. View

10.

Koren E, Fuchs Y . The bad seed: Cancer stem cells in tumor development and resistance. Drug Resist Updat. 2016; 28:1-12. DOI: 10.1016/j.drup.2016.06.006. View

11.

Wang W, Fang F, Ozes A, Nephew K . Targeting Ovarian Cancer Stem Cells by Dual Inhibition of HOTAIR and DNA Methylation. Mol Cancer Ther. 2021; 20(6):1092-1101. PMC: 8172444. DOI: 10.1158/1535-7163.MCT-20-0826. View

12.

Fioravanti R, Stazi G, Zwergel C, Valente S, Mai A . Six Years (2012-2018) of Researches on Catalytic EZH2 Inhibitors: The Boom of the 2-Pyridone Compounds. Chem Rec. 2018; 18(12):1818-1832. PMC: 7410397. DOI: 10.1002/tcr.201800091. View

13.

Linette G, Carreno B . Tumor-Infiltrating Lymphocytes in the Checkpoint Inhibitor Era. Curr Hematol Malig Rep. 2019; 14(4):286-291. PMC: 6642683. DOI: 10.1007/s11899-019-00523-x. View

14.

Wang L, Stadlbauer B, Lyu C, Buchner A, Pohla H . Shikonin enhances the antitumor effect of cabazitaxel in prostate cancer stem cells and reverses cabazitaxel resistance by inhibiting ABCG2 and ALDH3A1. Am J Cancer Res. 2020; 10(11):3784-3800. PMC: 7716147. View

15.

Ougolkov A, Bilim V, Billadeau D . Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2. Clin Cancer Res. 2008; 14(21):6790-6. PMC: 2690708. DOI: 10.1158/1078-0432.CCR-08-1013. View

16.

Dandawate P, Subramaniam D, Jensen R, Anant S . Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy. Semin Cancer Biol. 2016; 40-41:192-208. PMC: 5565737. DOI: 10.1016/j.semcancer.2016.09.001. View

17.

Hu S, Yu L, Li Z, Shen Y, Wang J, Cai J . Overexpression of EZH2 contributes to acquired cisplatin resistance in ovarian cancer cells in vitro and in vivo. Cancer Biol Ther. 2010; 10(8):788-95. DOI: 10.4161/cbt.10.8.12913. View

18.

Ge Y, Weygant N, Qu D, May R, Berry W, Yao J . Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer. Int J Cancer. 2018; 143(5):1162-1175. PMC: 8386112. DOI: 10.1002/ijc.31400. View

19.

Dimri M, Bommi P, Sahasrabuddhe A, Khandekar J, Dimri G . Dietary omega-3 polyunsaturated fatty acids suppress expression of EZH2 in breast cancer cells. Carcinogenesis. 2009; 31(3):489-95. PMC: 2832544. DOI: 10.1093/carcin/bgp305. View

20.

Hirata A, Hatano Y, Niwa M, Hara A, Tomita H . Heterogeneity in Colorectal Cancer Stem Cells. Cancer Prev Res (Phila). 2019; 12(7):413-420. DOI: 10.1158/1940-6207.CAPR-18-0482. View