Luteolin Promotes Apoptotic Cell Death Via Upregulation of Nrf2 Expression by DNA Demethylase and the Interaction of Nrf2 with P53 in Human Colon Cancer Cells

Overview

Journal Exp Mol Med

Specialties Biochemistry
Molecular Biology

Date 2019 Apr 17

PMID 30988303

Citations 63

Authors

Kyoung Ah Kang

Mei Jing Piao

Yu Jae Hyun

Ao Xuan Zhen

Suk Ju Cho

Mee Jung Ahn

Joo Mi Yi

Jin Won Hyun

Affiliations

Soon will be listed here.

Abstract

Luteolin, a dietary flavone, modulates various signaling pathways involved in carcinogenesis. In this study, we investigated the molecular mechanism that underlies the apoptotic effects of luteolin mediated by DNA demethylation of the nuclear factor erythroid 2-related factor 2 (Nrf2) promoter and the interaction of Nrf2 and p53, a tumor suppressor, in human colon cancer cells. Luteolin increased the expression of apoptosis-related proteins and antioxidant enzymes. In DNA methylation, luteolin inhibited the expression of DNA methyltransferases, a transcription repressor, and increased the expression and activity of ten-eleven translocation (TET) DNA demethylases, a transcription activator. Methyl-specific polymerase chain reaction and bisulfite genomic sequencing indicated that luteolin decreased the methylation of the Nrf2 promoter region, which corresponded to the increased mRNA expression of Nrf2. In addition, luteolin increased TET1 binding to the Nrf2 promoter, as determined using a chromatin immunoprecipitation (ChIP) assay. TET1 knockdown decreased the percentages of luteolin-treated cells in sub-G phase and cells with fragmented nuclei. Furthermore, complex formation between p53 and Nrf2 was involved in the apoptotic effects of luteolin. These results provide insight into the mechanism that underlies the anticancer effects of luteolin on colon cancer, which involve the upregulation of Nrf2 and its interaction with the tumor suppressor.

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References

Siegel R, Miller K, Jemal A . Cancer Statistics, 2017. CA Cancer J Clin. 2017; 67(1):7-30. DOI: 10.3322/caac.21387. View

van Engeland M, Derks S, Smits K, Meijer G, Herman J . Colorectal cancer epigenetics: complex simplicity. J Clin Oncol. 2011; 29(10):1382-91. DOI: 10.1200/JCO.2010.28.2319. View

Ally M, Al-Ghnaniem R, Pufulete M . The relationship between gene-specific DNA methylation in leukocytes and normal colorectal mucosa in subjects with and without colorectal tumors. Cancer Epidemiol Biomarkers Prev. 2009; 18(3):922-8. DOI: 10.1158/1055-9965.EPI-08-0703. View

Figueiredo J, Grau M, Wallace K, Levine A, Shen L, Hamdan R . Global DNA hypomethylation (LINE-1) in the normal colon and lifestyle characteristics and dietary and genetic factors. Cancer Epidemiol Biomarkers Prev. 2009; 18(4):1041-9. PMC: 2712652. DOI: 10.1158/1055-9965.EPI-08-0926. View

Coppede F . Epigenetic biomarkers of colorectal cancer: Focus on DNA methylation. Cancer Lett. 2011; 342(2):238-47. DOI: 10.1016/j.canlet.2011.12.030. View

Kim M, Lee J, Sidransky D . DNA methylation markers in colorectal cancer. Cancer Metastasis Rev. 2010; 29(1):181-206. DOI: 10.1007/s10555-010-9207-6. View

Perse M . Oxidative stress in the pathogenesis of colorectal cancer: cause or consequence?. Biomed Res Int. 2013; 2013:725710. PMC: 3666330. DOI: 10.1155/2013/725710. View

Li S, Yang G, Zhu X, Cheng L, Sun Y, Zhao Z . Combination of rapamycin and garlic-derived S-allylmercaptocysteine induces colon cancer cell apoptosis and suppresses tumor growth in xenograft nude mice through autophagy/p62/Nrf2 pathway. Oncol Rep. 2017; 38(3):1637-1644. DOI: 10.3892/or.2017.5849. View

Saw C, Huang M, Liu Y, Khor T, Conney A, Kong A . Impact of Nrf2 on UVB-induced skin inflammation/photoprotection and photoprotective effect of sulforaphane. Mol Carcinog. 2011; 50(6):479-86. DOI: 10.1002/mc.20725. View

10.

Xu C, Huang M, Shen G, Yuan X, Lin W, Khor T . Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res. 2006; 66(16):8293-6. DOI: 10.1158/0008-5472.CAN-06-0300. View

11.

Khor T, Huang M, Kwon K, Chan J, Reddy B, Kong A . Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res. 2006; 66(24):11580-4. DOI: 10.1158/0008-5472.CAN-06-3562. View

12.

Kwon Y . Luteolin as a potential preventive and therapeutic candidate for Alzheimer's disease. Exp Gerontol. 2017; 95:39-43. DOI: 10.1016/j.exger.2017.05.014. View

13.

Nabavi S, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Wozniak K . Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Res Bull. 2015; 119(Pt A):1-11. DOI: 10.1016/j.brainresbull.2015.09.002. View

14.

Pandurangan A, Mohd Esa N . Luteolin, a bioflavonoid inhibits colorectal cancer through modulation of multiple signaling pathways: a review. Asian Pac J Cancer Prev. 2014; 15(14):5501-8. DOI: 10.7314/apjcp.2014.15.14.5501. View

15.

Birt D, Hendrich S, Wang W . Dietary agents in cancer prevention: flavonoids and isoflavonoids. Pharmacol Ther. 2001; 90(2-3):157-77. DOI: 10.1016/s0163-7258(01)00137-1. View

16.

Lin Y, Shi R, Wang X, Shen H . Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 2008; 8(7):634-46. PMC: 2615542. DOI: 10.2174/156800908786241050. View

17.

Pandurangan A, Dharmalingam P, Ananda Sadagopan S, Ramar M, Munusamy A, Ganapasam S . Luteolin induces growth arrest in colon cancer cells through involvement of Wnt/β-catenin/GSK-3β signaling. J Environ Pathol Toxicol Oncol. 2013; 32(2):131-9. DOI: 10.1615/jenvironpatholtoxicoloncol.2013007522. View

18.

Zuo Q, Wu R, Xiao X, Yang C, Yang Y, Wang C . The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J Cell Biochem. 2018; 119(11):9573-9582. PMC: 6195448. DOI: 10.1002/jcb.27275. View

19.

Song I, Gu H, Han H, Lee N, Cha J, Son Y . Effects of 7-MEGA 500 on Oxidative Stress, Inflammation, and Skin Regeneration in HO-Treated Skin Cells. Toxicol Res. 2018; 34(2):103-110. PMC: 5903135. DOI: 10.5487/TR.2018.34.2.103. View

20.

Kang K, Bae J, Han K, Kim E, Kim T, Yi J . A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis. Int J Mol Sci. 2016; 17(8). PMC: 5000688. DOI: 10.3390/ijms17081291. View