Phenolic Acids Modulating Epigenetic Mechanisms in HepG2 Human Hepatoma Cells

Yıl 2024, Cilt: 14 Sayı: 2, 604 - 615, 01.06.2024

Doğukan Mutlu , Nevin Kaya Dikici , Naime Nur Bozbeyoğlu Kart , Şevki Arslan

https://doi.org/10.21597/jist.1427824

Öz

Phenolic compounds derived from plants exhibit an epigenetic modulatory impact in various cancer types by reversing DNA methylation patterns and chromatin modulation. In this study, caffeic acid (CA), ferulic acid (FA), and o-coumaric acid (OCA) mediated epigenetic alterations in hepatocarcinoma (HepG2) cells were investigated. For this purpose, changes DNMT enzyme activity and protein and mRNA levels of proteins involved in DNA methylation and histone acetylation were determined. The CA, FA, and OCA had cytotoxic activity at 48 h, with an EC50 value of 1.02, 3.1, and 5 mM in HepG2 cells, respectively. All compounds reduces the expression levels of histone acetyl transferases (HATs), histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). All these results showed that phenolic acids may be used in cancer therapy as a potential epigenetic modifier.

Anahtar Kelimeler

DNA Methylation, Caffeic acid, Ferulic acid, O-coumaric acid, Phenolic compods

Etik Beyan

In this study, the authors undertake that they comply with all the rules within the scope of the “Higher Education Institutions Scientific Research and Publication Ethics Directive” and that they do not take any of the actions under the heading “Actions Contrary to Scientific Research and Publication Ethics” of the relevant directive.

Destekleyen Kurum

Pamukkale Üniversitesi

Proje Numarası

2019FEBE018

Teşekkür

Pamukkale University Scientific Research Projects Coordination Department

Kaynakça

• Abe, S. K. & Inoue, M. (2021). Green tea and cancer and cardiometabolic diseases: a review of the current epidemiological evidence. European Journal of Clinical Nutrition, 75(6), 865-876.
• Agagunduz, D., Sahin, T.O., Yılmaz, B., Ekenci, K.D., Duyar Ozer, S. & Capasso, R. (2022). Cruciferous Vegetables and Their Bioactive Metabolites: from Prevention to Novel Therapies of Colorectal Cancer. Evidence-Based Complementary and Alternative Medicine, 2022, 1534083.
• Agarwal, A., Kansal, V., Farooqi, H., Prasad, R., Singh, V.K. (2023). Epigallocatechin Gallate (EGCG), an Active Phenolic Compound of Green Tea, Inhibits Tumor Growth of Head and Neck Cancer Cells by Targeting DNA Hypermethylation. Biomedicines, 11, 789.
• Anantharaju, P.G., Gowda, P.C., Vimalambike, M.G., & Madhunapantula, S.V. (2016). An overview on the role of dietary phenolics for the treatment of cancers. Nutrition Journal, 15.
• Arinc, E., Arslan, S. & Adali, O. (2005). Differential effects of diabetes on CYP2E1 and CYP2B4 proteins and associated drug metabolizing enzyme activities in rabbit liver. Archives of Toxicology, 79(8), 427-433.
• Balasubashini, M.S., Rukkumani, R., Viswanathan, P. & Menon, V.P. (2004). Ferulic acid alleviates lipid peroxidation in diabetic rats. Phytotherapy Research, 18, 310-314.
• Busch, C., Burkard, M., Leischner, C., Lauer, U.M., Frank, J. & Venturelli, S. (2015). Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clinical Epigenetics, 7(1), 64.
• Cheng, J.C., Dai, F., Zhou, B., Yang, L. & Liu, Z. L. (2007). Antioxidant activity of hydroxycinnamic acid derivatives in human low density lipoprotein: Mechanism and structure-activity relationship. Food Chemistry, 104(1), 132-139.
• Deans, C., & Maggert, K.A. (2015). What do you mean,“epigenetic”?. Genetics, 199(4), 887-896.
• Du, K., Li, Z., Fang, X., Cao, T. & Xu, Y. (2017). Ferulic acid promotes osteogenesis of bone marrow-derived mesenchymal stem cells by inhibiting microRNA-340 to induce β-catenin expression through hypoxia. European Journal of Cell Biology, 96(6), 496–503.
• El-Seedi, H.R., El-Said, A.M., Khalifa, S.A., Goransson, U., Bohlin, L., Borg-Karlson, A.K., Verpoorte, R. (2012). Biosynthesis, natural sources, dietary intake, pharmacokinetic properties, and biological activities of hydroxycinnamic acids. Journal of Agricultural and Food Chemistry, 60(44), 10877-10895.
• Feinberg, A.P., Koldobskiy, M.A. & Göndör, A. (2016). Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nature Reviews Genetics, 17(5), 284-299.
• Ferraz da Costa, D.C., Pereira Rangel, L., Quarti, J., Santos, R.A., Silva, J.L. & Fialho, E. (2020). Bioactive Compounds and Metabolites from Grapes and Red Wine in Breast Cancer Chemoprevention and Therapy. Molecules, 25(15), 3531.
• Gailhouste, L., Liew, L.C., Yasukawa, K., Hatada, I., Tanaka, Y., Nakagama, H. & Ochiya, T. (2018). Differentiation therapy by epigenetic reconditioning exerts antitumor effects on liver cancer cells. Molecular Therapy, 26, 1840-1854.
• Galicia-Moreno, M., Silva-Gomez, J.A., Lucano-Landeros, S., Santos, A., Monroy-Ramirez, H.C. & Armendariz-Borunda, J. (2021). Liver Cancer: Therapeutic Challenges and the Importance of Experimental Models. Canadian Journal of Gastroenterology and Hepatology, 2021, 8837811.
• Gutiérrez Mercado, Y.K., Mateos Díaz, J.C., Ojeda Hernández, D.D., López Gonzalez, F.J., Reza Zaldivar, E.E., Hernández Sapiens, M.A., Gómez Pinedo, U.A.; Estrada, R.S., Macías Carballo, M. & Canales Aguirre, A.A. (2022). Ortho-coumaric acid derivatives with therapeutic potential in a three-dimensional culture of the immortalised U-138 MG glioblastoma multiforme cell line. Neurology Perspectives, 2, 19-30.
• Hillyar, C., Rallis, K.S. & Varghese, J. (2020). Advances in Epigenetic Cancer Therapeutics. Cureus, 12(11), e11725.
• Ho, A.S., Turcan, S. & Chan, T.A. (2013). A Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management. OncoTargets and Therapy, 6, 223-322.
• Hsu, C.L., Wu, C.H., Huang, S.L. & Yen, G.C. (2009). Phenolic compounds rutin and o-coumaric acid ameliorate obesity induced by high-fat diet in rats. Journal of Agricultural and Food Chemistry, 57(2), 425-431.
• Hu, J., Cao, S., Zhang, Z., Wang, L., Wang, D., Wu, Q. & Li, L. (2020). Effects of caffeic acid on epigenetics in the brain of rats with chronic unpredictable mild stress. Molecular Medicine Reports, 22(6), 5358-5368.
• Izzo, S., Valeria, N. & Saverio, B. (2020) Flavonoids as Epigenetic Modulators for Prostate Cancer Prevention. Food Chemistry, 12(4), 1010.
• Jiang, A., Wang, X., Shan, X., Li, Y., Wang, P., Jiang, P., Feng, Q. (2015). Curcumin Reactivates Silenced Tumor Suppressor Gene RARβ by Reducing DNA Methylation. Phytotherapy Research, 29(8), 1237-1245.
• Kanwal, R. & Gupta, S. (2012). Epigenetic modifications in cancer. Clin Genet., 81(4), 303-311.
• Kedhari, S.M., Hussain, A., Haque, S., Raina, R. & Afroze, N. (2019). Quercetin modifies 5'CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells. Journal of Cellular Biochemistry, 120(10), 18357-18369.
• Kim, E.O., Min, K.J., Kwon, T.K., Um, B.H., Moreau, R.A., Choi, S.W. (2012). Anti-inflammatory activity of hydroxycinnamic acid derivatives isolated from corn bran in lipopolysaccharide-stimulated Raw 264.7 macrophages. Food and Chemical Toxicology, 50(5), 1309-1316.
• Kumar, V., Dhanjal, J.K., Sari, A.N., Khurana, M., Kaul, S.C., Wadhwa, R. & Sundar, D. (2023). Effect of Withaferin-A, Withanone, and Caffeic Acid Phenethyl Ester on DNA Methyltransferases: Potential in Epigenetic Cancer Therapy. Current Topics in Medicinal Chemistry, 23.
• Kurt-Kızıldoğan, A., Akarsu, N., Otur, Ç., Kivrak, A., Aslan-Ertas, N., Arslan, S., Mutlu, D., Konus, M., Yılmaz, C., Cetin, D., Topal, T. & Şahin, N. (2022). A Novel 4H-Chromen-4-One Derivative from Marine Streptomyces ovatisporus S4702T as Potential Antibacterial and Anti-Cancer Agent. Anti-Cancer Agents in Medicinal Chemistry, 22(2), 362-370.
• Laemmli U.K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680–685.
• Li, W., Li, N., Tang, Y., Li, B., Liu, L., Zhang, X., Fu, H. & Duan, J.A. (2012). Biological activity evaluation and structure-activity relationships analysis of ferulic acid and caffeic acid derivatives for anticancer. Bioorganic & Medicinal Chemistry Letters, 22(19), 6085-6088.
• Liman, R., Kursunlu, A. N., Ozmen, M., Arslan, S., Mutlu, D., Istifli, E. S., & Acikbas, Y. (2022). Synthesis of Water Soluble Symmetric and Asymmetric Pillar [5] Arene Derivatives: Cytotoxicity, Apoptosis and Molecular Docking Studies. Journal of Molecular Structure, 1265, 133482.
• Mondal, P., Natesh, J., Penta, D. & Meeran, S.M. (2020). Progress and promises of epigenetic drugs and epigenetic diets in cancer prevention and therapy: A clinical update. Seminars in Cancer Biology, 83, 503-522.
• Mutlu, D., Secme, M. & Arslan, S. (2023). Anticancer Effects of Alpha-lipoic Acid on A172 and U373 Human Glioblastoma Cells. Journal of the Institute of Science and Technology, 13(2), 851- 857.
• Nandakumar, V., Vaid, M., Katiyar, S.K. (2011). (-)-Epigallocatechin-3-gallate reactivates silenced tumor suppressor genes, Cip1/p21 and p16INK4a, by reducing DNA methylation and increasing histones acetylation in human skin cancer cells. Carcinogenesis, 32(4), 537-44.
• Nasr Bouzaiene, N, Kilani Jaziri, S., Kovacic, H., Chekir-Ghedira, L., Ghedira, K. & Luis, J. (2015). The effects of caffeic, coumaric and ferulic acids on proliferation, superoxide production, adhesion and migration of human tumor cells in vitro. European Journal of Pharmacology, 766, 99-105.
• Olthof, M.R., Hollman, P.C. & Katan, M.B. (2001). Chlorogenic acid and caffeic acid are absorbed in humans. The Journal of Nutrition, 131(1), 66-71.
• Omene, C., Kalac, M., Wu, J., Marchi, E., Frenkel, K., O'Connor, O.A. (2013). Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. Journal of Cancer Science and Therapy, 5(10), 334-342.
• Ong, T.P., Moreno, F.S. & Ross, S.A. (2012). Targeting the epigenome with bioactive food components for cancer prevention. Journal of Nutrigenetics and Nutrigenomics, 4(5), 275-292.
• Rodríguez-García, C., Sánchez-Quesada, C. & Gaforio, J.J. (2019). Dietary Flavonoids as Cancer Chemopreventive Agents: An Updated Review of Human Studies. Antioxidants, 8, 137.
• Saenglee, S., Jogloy, S., Patanothai, A., Leid, M. & Senawong, T. (2016). Cytotoxic effects of peanut phenolics possessing histone deacetylase inhibitory activity in breast and cervical cancer cell lines. Pharmacological Reports, 68(6), 1102-1110.
• Sahin, C., Mutlu, D., Nasirli, F., Mahmoudi, G., Zubkov, F.I., Arslan, S. & Dogan, N.M. (2021). New iridium bis-terpyridine complexes: synthesis, characterization, antibiofilm and anticancer potentials. Biometals, 34(3), 701-713.
• Selvakumar, P., Badgeley, A., Murphy, P., Anwar, H., Sharma, U., Lawrence, K. & Lakshmikuttyamma, A. (2020). Flavonoids and Other Polyphenols Act as Epigenetic Modifiers in Breast Cancer. Nutrients, 12(3), 761.
• Sen, A., Atmaca, P., Terzioglu, G. & Arslan, S. (2013). Anticarcinogenic Effect and Carcinogenic Potential of the Dietary Phenolic Acid: O-Coumaric Acid. Natural Product Communications, 8(9), 1269-1274.
• Sen, P., Ganguly, P. & Ganguly, N. (2018). Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer. Oncology Letters, 15(1), 11-22.
• Shankar, E., Kanwal, R., Candamo, M. & Gupta, S. (2016). Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Seminars in Cancer Biology, 40-41, 82-99.
• Shin, E.J., Jo, S., Choi, H.K., Choi, S., Byun, S. & Lim, T.G. (2019). Caffeic Acid Phenethyl Ester Inhibits UV-Induced MMP-1 Expression by Targeting Histone Acetyltransferases in Human Skin. International Journal of Molecular Sciences, 20(12), 3055.
• Shukla, S., Meeran, S.M. & Katiyar, S.K. (2014). Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention. Cancer Letters, 355(1), 9-17.
• Song, S.H., Han, S.W. & Bang, Y.J. (2011). Epigenetic-based therapies in cancer. Drugs, 71, 2391-2403.
• Sultana, R. (2012). Ferulic acid ethyl ester as a potential therapy in neurodegenerative disorders. Biochimica et Biophysica Acta, 1822(5), 748-752.
• Thakur, V.S., Deb, G., Babcook, M.A. & Gupta, S. (2014). Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention. The AAPS Journal, 16(1), 151-163.
• Velkov, Z., Balabanova, E. & Tadjer, A. (2007). Radical scavenging activity prediction of o-coumaric acid thioamide. Journal of Molecular Structure, 1-3, 133-138.
• Venturelli, S., Berger, A., Böcker, A., Busch, C., Weiland, T., Noor, S., Leischner, C., Schleicher, S., Mayer, M., Weiss, T.S., Bischoff, S.C., Lauer, U.M. & Bitzer, M. (2013). Resveratrol as a pan-HDAC inhibitor alters the acetylation status of histone [corrected] proteins in human-derived hepatoblastoma cells. PLOS One, 8(8), e73097.
• Wahid, B., Ali, A., Rafique, S. & Idrees, M. (2017). New Insights into the Epigenetics of Hepatocellular Carcinoma. BioMed Research International, 2017, 1609575.
• Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. & Schrenk, D. (2008). Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. The Journal of Nutritional Biochemistry, 19(9), 587-593.
• Wang, A., Xu, Q., Sha, R., Bao, T., Xi, X. & Guo, G. (2021). MicroRNA-29a inhibits cell proliferation and arrests cell cycle by modulating p16 methylation in cervical cancer. Oncology Letters, 21(4), 272.
• Wang, F., Lu, W., Zhang, T., Dong, J., Gao, H., Li, P., Wang, S. & Zhang, J. (2013). Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors. Bioorganic & Medicinal Chemistry, 21(22), 6973-6980.
• Wang, L., Lu, M., Yi, M., Chen, L., Shen, J., Li, Z., Li, L., Yang, Y., Zhang, J. & Li, Y. (2015). Caffeic acid attenuates the autocrine IL-6 in hepatocellular carcinoma via the epigenetic silencing of the NF-κB-IL-6-STAT-3 feedback loop. RSC Advances, 5, 52952–52957.
• Wang, P., Yamabe, N., Hong, C.J., Bai, H.W. & Zhu, B.T. (2020). Caffeic acid phenethyl ester, a coffee polyphenol, inhibits DNA methylation in vitro and in vivo. European Journal of Pharmacology, 887, 173464.
• Yao, H., Xu, W., Shi, X. & Zhang, Z. (2011). Dietary flavonoids as cancer prevention agents. Journal of Environmental Science and Health., 29(1), 1-31.
• Yu, J., Peng, Y., Wu, L.C., Xie, Z., Deng, Y. & Hughes, T. (2013). Curcumin Down-Regulates DNA Methyltransferase 1 and Plays an Anti-Leukemic Role in Acute Myeloid Leukemia. PLOS One, 8(2), e55934.
• Zhang, X., Lin, D., Jiang, R., Li, H., Wan, J. & Li, H. (2016). Ferulic acid exerts antitumor activity and inhibits metastasis in breast cancer cells by regulating epithelial to mesenchymal transition. Oncology Reports, 36(1), 271-278.
• Zhang, Y. (2015). Cancer Epigenetics: Risk Assessment, Diagnosis, Treatment, and Prognosis. Detection of epigenetic aberrations in the development of hepatocellular carcinoma. Methods in Molecular Biology, 1238, 709–731.