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

• Published in: Experimental & molecular medicine Vol. 51; no. 4; pp. 1 - 14
• Main Authors: Kang, Kyoung Ah, Piao, Mei Jing, Hyun, Yu Jae, Zhen, Ao Xuan, Cho, Suk Ju, Ahn, Mee Jung, Yi, Joo Mi, Hyun, Jin Won
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.04.2019; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13; 13/2; 13/31; 14; 14/34; 631/67/1504/1885/1393; 631/80/82/23; Antioxidants; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biomedical and Life Sciences; Biomedicine; Bisulfite; Blotting, Western; Carcinogenesis; Cell death; Cell Survival; Chromatin; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Demethylation; Deoxyribonucleic acid; DNA; DNA demethylase; DNA methylation; DNA Methylation - drug effects; DNA Methylation - genetics; G1 phase; Gene expression; HT29 Cells; Humans; Immunoprecipitation; Luteolin - pharmacology; Medical Biochemistry; Molecular Medicine; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2 protein; p53 Protein; Polymerase chain reaction; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Stem Cells; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Up-regulation; Whole genome sequencing; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-019-0238-y

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 1 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. Cancer: Cell-killing plant compound exerts antioxidant effects A molecule found in fruits, vegetables and herbs helps kill colon cancer cells by activating a master regulator of detoxifying enzymes. Jin Won Hyun from Jeju National University School of Medicine in South Korea and colleagues treated human colon cancer cells with luteolin, a molecule that occurs naturally in many food plants. They showed that luteolin increased the levels of proteins involved in cell death and antioxidant responses by causing DNA-modifying enzymes to strip suppressive chemical markers off the gene encoding Nrf2, a protein that regulates antioxidant effects. Nrf2 levels subsequently increased and the protein interacted with the tumor suppressor p53 to facilitate destruction of the colon cancer cells. The findings offer a mechanistic basis for using luteolin to help prevent and treat cancer.