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-G1 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.
Highlights
Colon cancer is a major cause of morbidity and mortality worldwide[1]
Primary antibodies against p53, p21, Bcl-2, Bax, caspase-9, glutamate cysteine ligase catalytic (GCLc), glutathione synthetase (GSS), catalase, heme oxygenase-1 (HO-1), Nrf[2], TET1, TET2, TET3, DNMT3B, and actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA)
TET1 upregulates Nrf[2] expression in luteolin-treated cells The results shown in Fig. 4 suggest that the binding ability of DNA methyltransferase (DNMT) and ten-eleven translocation (TET) to the Nrf[2] promoter might be decreased and increased, respectively
Summary
Colon cancer is a major cause of morbidity and mortality worldwide[1]. The accumulation of genetic and epigenetic alterations in the normal colon leads to the transformation of the normal colonic epithelium into colon adenocarcinomas[2]. Accumulating evidence indicates that DNA methylation of gene promoters increases in the colonic mucosa of colon cancer patients[3,4]. Aberrant DNA methylation is an important driving factor for colon cancer progression and metastasis. CXCL12, which encodes a chemokine ligand, is aberrantly methylated in colon cancer patients; this aberrant methylation promotes the metastatic behavior of colon cancer cell lines[5]. Multiple inactive genes, including TIMP3, ID4, and IRF8, with methylated promoter regions provide a clonal growth advantage, which results in more severe malignant phenotypes[5,6]
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