Quercetin Suppresses Glioma Stem Cells via Activating p16-INK4 Gene Expression through Epigenetic Regulation
- Autores: Li J.1, Li J.1, Guo E.1
-
Afiliações:
- , The Second Hospital of Hebei Medical University
- Edição: Volume 25, Nº 14 (2025)
- Páginas: 1041-1048
- Seção: Chemistry
- URL: https://genescells.com/1871-5206/article/view/694442
- DOI: https://doi.org/10.2174/0118715206332048241126095207
- ID: 694442
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Resumo
Objectives:Our study aimed to explore the effects of quercetin on glioma stem cells in patients with brain tumors.
Methods: Human glioblastoma cell line, U373MG, or glioma stem cell lines, were treated with quercetin. Cell viability was determined by using the cell counting kit 8 assays. Cell apoptosis was determined by using the Annexin- V reagent. Western blotting and qPCR were used to detect the protein and mRNA levels of cyclindependent kinase inhibitor 2A (p16INK4a). Chromatin immunoprecipitation analysis was used to determine the enrichment of H3K27me3 on the p16-INK4 locus with or without quercetin.
Results: Treatment with quercetin inhibited cell viability and induced cell apoptosis in U373MG cells. Moreover, treatment with quercetin inhibited the cell viability of four glioma stem cell lines (G3, G10, G15, and G17) from brain tumor samples at high concentrations while having no obvious effects for the other two glioma stem cell lines (G9 and G21). Treatment with quercetin increased the mRNA and protein levels of p16- INK4 in glioma stem cell lines. The study of the underlying mechanism revealed that treatment with quercetin reduced H3K27me3 (an epigenetic modification to the DNA packaging protein histone H3) levels at the p16-INK4 locus.
Conclusions:In conclusion, quercetin inhibits glioma cell growth by activating p16-INK4 gene expression through epigenetic regulation.
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Sobre autores
Jianliang Li
, The Second Hospital of Hebei Medical University
Email: info@benthamscience.net
Jingchen Li
, The Second Hospital of Hebei Medical University
Email: info@benthamscience.net
Erkun Guo
, The Second Hospital of Hebei Medical University
Autor responsável pela correspondência
Email: info@benthamscience.net
Bibliografia
- Wirsching, H.G.; Galanis, E.; Weller, M. Glioblastoma. Handb. Clin. Neurol., 2016, 134, 381-397. doi: 10.1016/B978-0-12-802997-8.00023-2 PMID: 26948367
- Tamimi, A.F.; Juweid, M. Epidemiology and outcome of glioblastoma.In: Glioblastoma; Exon Publications, 2017. doi: 10.15586/codon.glioblastoma.2017.ch8
- Davis, M. Glioblastoma: Overview of disease and treatment. Clin. J. Oncol. Nurs., 2016, 20(5)(Suppl.), S2-S8. doi: 10.1188/16.CJON.S1.2-8 PMID: 27668386
- Preusser, M.; de Ribaupierre, S.; Wöhrer, A.; Erridge, S.C.; Hegi, M.; Weller, M.; Stupp, R. Current concepts and management of glioblastoma. Ann. Neurol., 2011, 70(1), 9-21. doi: 10.1002/ana.22425 PMID: 21786296
- Tan, A.C.; Ashley, D.M.; López, G.Y.; Malinzak, M.; Friedman, H.S.; Khasraw, M. Management of glioblastoma: State of the art and future directions. CA Cancer J. Clin., 2020, 70(4), 299-312. doi: 10.3322/caac.21613 PMID: 32478924
- Fernandes, C.; Costa, A.; Osório, L.; Lago, R.C.; Linhares, P.; Carvalho, B.; Caeiro, C. Current standards of care in glioblastoma therapy.In: Glioblastoma; Exon Publications, 2017, pp. 197-241. doi: 10.15586/codon.glioblastoma.2017.ch11
- Ostrom, Q.T.; Cioffi, G.; Gittleman, H.; Patil, N.; Waite, K.; Kruchko, C.; Barnholtz-Sloan, J.S. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol., 2019, 21(Suppl. 5), v1-v100. doi: 10.1093/neuonc/noz150 PMID: 31675094
- Surguchov, A.; Bernal, L.; Surguchev, A.A. Phytochemicals as regulators of genes involved in synucleinopathies. Biomolecules, 2021, 11(5), 624. doi: 10.3390/biom11050624 PMID: 33922207
- Lesjak, M.; Beara, I.; Simin, N.; Pintać, D.; Majkić, T.; Bekvalac, K.; Orčić, D.; Mimica-Dukić, N. Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J. Funct. Foods, 2018, 40, 68-75. doi: 10.1016/j.jff.2017.10.047
- Kelly, G.S. Quercetin. Monograph. Altern. Med. Rev., 2011, 16(2), 172-194. PMID: 21649459
- Gormaz, J.; Quintremil, S.; Rodrigo, R. Cardiovascular disease: A target for the pharmacological effects of quercetin. Curr. Top. Med. Chem., 2015, 15(17), 1735-1742. doi: 10.2174/1568026615666150427124357 PMID: 25915608
- Tavana, E.; Mollazadeh, H.; Mohtashami, E.; Modaresi, S.M.S.; Hosseini, A.; Sabri, H.; Soltani, A.; Javid, H.; Afshari, A.R.; Sahebkar, A. Quercetin: A promising phytochemical for the treatment of glioblastoma multiforme. Biofactors, 2020, 46(3), 356-366. doi: 10.1002/biof.1605 PMID: 31880372
- Tsiailanis, A.D.; Renziehausen, A.; Kiriakidi, S.; Vrettos, E.I.; Markopoulos, G.S.; Sayyad, N.; Hirmiz, B.; Aguilar, M.I.; Del Borgo, M.P.; Kolettas, E.; Widdop, R.E.; Mavromoustakos, T.; Crook, T.; Syed, N.; Tzakos, A.G. Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid. Free Radic. Biol. Med., 2020, 160, 391-402. doi: 10.1016/j.freeradbiomed.2020.08.007 PMID: 32822744
- Kim, H.I.; Lee, S.J.; Choi, Y.J.; Kim, M.J.; Kim, T.Y.; Ko, S.G. Quercetin induces apoptosis in glioblastoma cells by suppressing Axl/IL-6/STAT3 signaling pathway. Am. J. Chin. Med., 2021, 49(3), 767-784. doi: 10.1142/S0192415X21500361 PMID: 33657989
- Liu, Y.; Tang, Z.G.; Lin, Y.; Qu, X.G.; Lv, W.; Wang, G.B.; Li, C.L. Effects of quercetin on proliferation and migration of human glioblastoma U251 cells. Biomed. Pharmacother., 2017, 92, 33-38. doi: 10.1016/j.biopha.2017.05.044 PMID: 28528183
- Zamin, L.L.; Filippi-Chiela, E.C.; Vargas, J.; Demartini, D.R.; Meurer, L.; Souza, A.P.; Bonorino, C.; Salbego, C.; Lenz, G. Quercetin promotes glioma growth in a rat model. Food Chem. Toxicol., 2014, 63, 205-211. doi: 10.1016/j.fct.2013.11.002 PMID: 24252772
- Rayess, H.; Wang, M.B.; Srivatsan, E.S. Cellular senescence and tumor suppressor gene p16. Int. J. Cancer, 2012, 130(8), 1715-1725. doi: 10.1002/ijc.27316 PMID: 22025288
- Jurisic, V.; Obradovic, J.; Nikolic, N.; Javorac, J.; Perin, B.; Milasin, J. Analyses of P16INK4a gene promoter methylation relative to molecular, demographic and clinical parameters characteristics in non-small cell lung cancer patients: A pilot study. Mol. Biol. Rep., 2023, 50(2), 971-979. doi: 10.1007/s11033-022-07982-1 PMID: 36378420
- Kitamura, H.; Takemura, H.; Minamoto, T. Tumor p16INK4 gene expression and prognosis in colorectal cancer. Oncol. Rep., 2018, 41(2), 1367-1376. doi: 10.3892/or.2018.6884 PMID: 30483798
- Zhao, W.; Huang, C.C.; Otterson, G.A.; Leon, M.E.; Tang, Y.; Shilo, K.; Villalona, M.A. Altered p16(INK4) and RB1 expressions are associated with poor prognosis in patients with nonsmall cell lung cancer. J. Oncol., 2012, 2012, 1-7. doi: 10.1155/2012/957437 PMID: 22619677
- Tan, S.; Wang, C.; Lu, C.; Zhao, B.; Cui, Y.; Shi, X.; Ma, X. Quercetin is able to demethylate the p16INK4a gene promoter. Chemotherapy, 2009, 55(1), 6-10. doi: 10.1159/000166383 PMID: 18974642
- Jang, E.; Kim, I.Y.; Kim, H.; Lee, D.M.; Seo, D.Y.; Lee, J.A.; Choi, K.S.; Kim, E. Quercetin and chloroquine synergistically kill glioma cells by inducing organelle stress and disrupting Ca2+ homeostasis. Biochem. Pharmacol., 2020, 178114098 doi: 10.1016/j.bcp.2020.114098 PMID: 32540484
- Pollard, S.M.; Yoshikawa, K.; Clarke, I.D.; Danovi, D.; Stricker, S.; Russell, R.; Bayani, J.; Head, R.; Lee, M.; Bernstein, M.; Squire, J.A.; Smith, A.; Dirks, P. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell, 2009, 4(6), 568-580. doi: 10.1016/j.stem.2009.03.014 PMID: 19497285
- Zhou, D.; Alver, B.M.; Li, S.; Hlady, R.A.; Thompson, J.J.; Schroeder, M.A.; Lee, J.H.; Qiu, J.; Schwartz, P.H.; Sarkaria, J.N.; Robertson, K.D. Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues. Genome Biol., 2018, 19(1), 43. doi: 10.1186/s13059-018-1420-6 PMID: 29587824
- Liu, C.; Zhao, J.; Liu, Y.; Huang, Y.; Shen, Y.; Wang, J.; Sun, W.; Sun, Y. A novel pentacyclic triterpenoid, Ilexgenin A, shows reduction of atherosclerosis in apolipoprotein E deficient mice. Int. Immunopharmacol., 2016, 40, 115-124. doi: 10.1016/j.intimp.2016.08.024 PMID: 27588911
- Mohammad, F.; Weissmann, S.; Leblanc, B.; Pandey, D.P.; Højfeldt, J.W.; Comet, I.; Zheng, C.; Johansen, J.V.; Rapin, N.; Porse, B.T.; Tvardovskiy, A.; Jensen, O.N.; Olaciregui, N.G.; Lavarino, C.; Suñol, M.; de Torres, C.; Mora, J.; Carcaboso, A.M.; Helin, K. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat. Med., 2017, 23(4), 483-492. doi: 10.1038/nm.4293 PMID: 28263309
- Sanai, N.; Alvarez-Buylla, A.; Berger, M.S. Neural stem cells and the origin of gliomas. N. Engl. J. Med., 2005, 353(8), 811-822. doi: 10.1056/NEJMra043666 PMID: 16120861
- Goffart, N.; Kroonen, J.; Rogister, B. Glioblastoma-initiating cells: Relationship with neural stem cells and the micro-environment. Cancers (Basel), 2013, 5(3), 1049-1071. doi: 10.3390/cancers5031049 PMID: 24202333
- Liu, L.; Yin, S.; Brobbey, C.; Gan, W. Ubiquitination in cancer stem cell: Roles and targeted cancer therapy. STEMedicine, 2020, 1(3)e37 doi: 10.37175/stemedicine.v1i3.37
- Matarredona, E.R.; Pastor, A.M. Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells. Therapeutic implications. Front. Oncol., 2019, 9, 779. doi: 10.3389/fonc.2019.00779 PMID: 31482066
- Bagó, J.R.; Alfonso-Pecchio, A.; Okolie, O.; Dumitru, R.; Rinkenbaugh, A.; Baldwin, A.S.; Miller, C.R.; Magness, S.T.; Hingtgen, S.D. Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nat. Commun., 2016, 7(1), 10593. doi: 10.1038/ncomms10593 PMID: 26830441
- Liggett, W.H.; Sidransky, D. Role of the p16 tumor suppressor gene in cancer. J. Clin. Oncol., 1998, 16(3), 1197-1206. doi: 10.1200/JCO.1998.16.3.1197 PMID: 9508208
- Rocco, J.W.; Sidransky, D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp. Cell Res., 2001, 264(1), 42-55. doi: 10.1006/excr.2000.5149 PMID: 11237522
- Foulkes, W.D.; Flanders, T.Y.; Pollock, P.M.; Hayward, N.K. The CDKN2A (p16) gene and human cancer. Mol. Med., 1997, 3(1), 5-20. doi: 10.1007/BF03401664 PMID: 9132280
- Esteller, M.; González, S.; Risques, R.A.; Marcuello, E.; Mangues, R.; Germà, J.R.; Herman, J.G.; Capellà, G.; Peinado, M.A. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J. Clin. Oncol., 2001, 19(2), 299-304. doi: 10.1200/JCO.2001.19.2.299 PMID: 11208819
- Mohseny, A.B.; Tieken, C.; van der Velden, P.A.; Szuhai, K.; de Andrea, C.; Hogendoorn, P.C.W.; Cleton-Jansen, A.M. Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma. Genes Chromosomes Cancer, 2010, 49(12), 1095-1103. doi: 10.1002/gcc.20817 PMID: 20737480
- Reed, A.L.; Califano, J.; Cairns, P.; Westra, W.H.; Jones, R.M.; Koch, W.; Ahrendt, S.; Eby, Y.; Sewell, D.; Nawroz, H.; Bartek, J.; Sidransky, D. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res., 1996, 56(16), 3630-3633. PMID: 8705996
- Kamiryo, T.; Tada, K.; Shiraishi, S.; Shinojima, N.; Nakamura, H.; Kochi, M.; Kuratsu, J.; Saya, H.; Ushio, Y. Analysis of homozygous deletion of the p16 gene and correlation with survival in patients with glioblastoma multiforme. J. Neurosurg., 2002, 96(5), 815-822. doi: 10.3171/jns.2002.96.5.0815 PMID: 12005388
- Asgharian, P.; Tazekand, A.P.; Hosseini, K.; Forouhandeh, H.; Ghasemnejad, T.; Ranjbar, M.; Hasan, M.; Kumar, M.; Beirami, S.M.; Tarhriz, V.; Soofiyani, S.R.; Kozhamzharova, L.; Sharifi-Rad, J.; Calina, D.; Cho, W.C. Potential mechanisms of quercetin in cancer prevention: Focus on cellular and molecular targets. Cancer Cell Int., 2022, 22(1), 257. doi: 10.1186/s12935-022-02677-w PMID: 35971151
- Carlos-Reyes, Á.; López-González, J.S.; Meneses-Flores, M.; Gallardo-Rincón, D.; Ruíz-García, E.; Marchat, L.A.; Astudillo-de la Vega, H.; Hernández de la Cruz, O.N.; López-Camarillo, C. Dietary compounds as epigenetic modulating agents in cancer. Front. Genet., 2019, 10, 79. doi: 10.3389/fgene.2019.00079 PMID: 30881375
- Harris, Z.; Donovan, M.G.; Branco, G.M.; Limesand, K.H.; Burd, R. Quercetin as an emerging anti-melanoma agent: A four-focus area therapeutic development strategy. Front. Nutr., 2016, 3, 48. doi: 10.3389/fnut.2016.00048 PMID: 27843913
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