Further, the modulations different of histone methylation and acetylation by chrysin might initiate several levels of chromatin modification in the multiple sites such as ?684 to ?692, ?2549 to ?2557 required for transcrip tional regulation of p21 gene. The histone methyla tion functions to regulate the chromatin organization directly by affecting higher order packaging of chromatin fiber and is required for the gene transcription and DNA repair mechanism by changing the accessibility of DNA to several transcriptional factors. It is known that histone lysine methylation of H3k4 is associated with promoters of actively transcribed genes where as H3K9 lysine methylation is associated with heterochroma tin formation. Jumonji C domain containing enzymes constitute the largest class of histone demthylases which includes JMJD2c and LSD1 and is linked particularly in prostate cancer.

Thus we propose that histone tail modifications by the plant chrysin such as methylation and acetylation of lysine are the prominent epigenetic marks that regulate the binding of different transcriptional factors. Consistent with this notion, histone modification will allow the recruitment of STAT family of proteins at STAT binding sites in the p21WAF1 promoter. The mode of action of chrysin is distinct from the known HDAC inhibitors such as SAHA and TSA. Treat ment of SAHA and TSA inhibits LSD1, the known his tone lysine demethylase I which demethylate both mono as well as dimethyl lysine 4 of histone H3 that lead to the chromatin modification at the p21WAF1 promoter.

But function of chrysin is unique and novel from known HDAC inhibitors which decrease the H3k9 dimethylation at the p21WAF1 promoter. Emerging evidence has indicated p53 independent tran scriptional activation of p21 include STAT1, MyoD1 and BRCA1. Precisely, this study also shows a new regula tory relationship between p21WAF1 and STAT proteins via epigenetic modulation. The changes in the histone code of the chromatin in or near STAT binding sites by the chrysin can increase accessibility of the STAT 1 3 proteins that lead to activate STAT mediated induction of p21WAF1 expression. Earlier studies indicated the involvement of STAT 1 dependent and p53 independent expression of p21 controlling apoptosis. These results not only suggest that chromatin remodeling within the STAT responsive sites can control transcriptional regula tion but also demonstrate that modification in core histone tails by chrysin might activate STAT signals in A375 cells. STAT activated signals in response to IFN gamma are dir ectly involved in regulating AV-951 p21WAF1 expression.