The triterpenoid corosolic acid blocks transformation and epigenetically reactivates

Corosolic acid (CRA, Figure 1A), a triterpenoid also known as 2α-hydroxyursolic acid, is found in various plants, including Schisandra chinensis, Eriobotrya japonica, Lagerstroemia speciosa L., Orthosiphon stamineus and Weigela subsessilis. It has been demonstrated that CRA has significant anti-diabetes, anti-obesity and anti-atherosclerosis activities, and CRA also exhibits anticancer activities against various cancer cell lines.

orosolic acid (CRA) is found in various plants and has been used as a health food supplement worldwide. Although it has been reported that CRA exhibits significant anticancer activity, the effect of this compound on prostate cancer remains unknown.  In this study, we investigated the effect of CRA on cellular transformation and the  reactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) through epigenetic regulation in TRAMP-C1 prostate cells. Specifically, we found that CRA inhibited  anchorage-independent growth of prostate cancer TRAMP-C1 cells but not Nrf2 knockout prostate cancer TRAMP-C1 cells. Moreover, CRA induced mRNA and  protein expression of Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase-1(NQO1). Bisulfate genomic sequencing and methylated DNA immunoprecipitation results revealed that CRA treatment decreased the level of methylation of the first five CpG sites of the Nrf2 promoter. Histone modification was analyzed using a chromatin  immunoprecipitation (ChIP) assay, which revealed that CRA treatment increased the acetylation of histone H3 lysine 27 (H3K27ac) while decreasing the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter region of Nrf2. Furthermore, CRA treatment attenuated the protein expression of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). These findings indicate that CRA has a significant anticancer effect in TRAMP-C1 cells, which could be partly attributed to epigenetics including its ability to epigenetically restore the expression of Nrf2.

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