Quercetin Suppresses Glioma Stem Cells via Activating p16-INK4 Gene Expression through Epigenetic Regulation


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Аннотация

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.

Об авторах

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

Автор, ответственный за переписку.
Email: info@benthamscience.net

Список литературы

  1. 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
  2. Tamimi, A.F.; Juweid, M. Epidemiology and outcome of glioblastoma.In: Glioblastoma; Exon Publications, 2017. doi: 10.15586/codon.glioblastoma.2017.ch8
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Kelly, G.S. Quercetin. Monograph. Altern. Med. Rev., 2011, 16(2), 172-194. PMID: 21649459
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
  32. 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
  33. 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
  34. 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
  35. 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
  36. 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
  37. 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
  38. 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
  39. 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
  40. 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
  41. 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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