Colorectal cancer remains a leading malignancy in humans. The importance of epigenetic modification in the development of this disease is now being recognized. The reversible and dynamic nature of epigenetic modifications provides a promising strategy in colorectal cancer chemoprevention and treatment. Luteolin (LUT), a flavone dietary phytochemical, can modulate various signaling pathways involved in carcinogenesis. Many studies have demonstrated that LUT inhibits colorectal carcinogenesis by activating the Nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant-responsive element (ARE) pathway. However, the potential epigenetic mechanism underlying Nrf2/ARE pathway activation remains unclear. In this study, we aimed to explore the anticancer potential of LUT in human colon cancer cells and the epigenetic regulation of the Nrf2/ARE pathway. Specifically, our data showed that LUT suppressed cell proliferation and cellular transformation of HCT116 and HT29 cells in a dose-dependent manner. Additionally, quantitative real-time polymerase chain reaction and Western blot analysis were performed to determine the mRNA and protein expression of Nrf2 and its downstream genes after LUT treatment. Bisulfite genomic sequencing revealed that methylation of the Nrf2 promoter region was decreased by LUT, corresponding with the increased mRNA expression of Nrf2. Decreased protein levels and enzyme activities of epigenetic modifying enzymes, such as DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), were also observed in LUT-treated HCT116 cells. In summary, our findings suggest that LUT may exert its antitumor activity in part via epigenetic modifications of the Nrf2 gene with subsequent induction of its downstream antioxidative stress pathway.
Keywords: DNA methylation; colorectal cancer; luteolin (LUT); nuclear factor erythroid 2-related factor 2 (Nrf2).
© 2018 Wiley Periodicals, Inc.