The HDAC activity within the cells can be altered by direct inhibition of HDAC enzyme as well as changes in HDAC protein expression. We found decrease in the level of HDAC 8 protein as well as enzyme activity in the chrysin sellekchem treated melanoma cells. Similarly decrease in activity and protein levels of HDACs was observed in the case of recent studies on HDAC inhibitors such as Allyl mercap tan, NBM HD 1, apigenin. It is a well established concept that HDAC inhibitors induce apop totic response in a P53 dependent and independent ways. In our study we have observed induction of p21 protein and mRNA in A375 cells with drastic reduction in the p53 protein, level indicating chrysin mediated p21 induction is independent of p53 status in A375 melan oma cells.
The p53 independent induction of p21 activity was observed in studies on TSA and Apigenin, a well known flavonoid. This mechanism was reported to be cell type dependent. Typical to HDAC inhibitor, chrysin and its analogues can arrest cell growth and induce p21WAF1 transcription, but its mechanism of action is quite different from known HDAC inhibitors. It selectively enhances the accumulation of acetylated histones and STAT proteins at the STAT binding site of the p21WAF1 promoter. Indeed, the novelty of the plant chrysin is to delocalize methyl group from the histone H3 lysine 9 from the STAT response element. Reduced histone methylation by treatment with chrysin acts sequentially or in concert with the ele vated histone acetylation that might form a complex his tone code.
Such fine tuning in the chromatin structure precisely in STAT responsive sequence might recognize the non histone proteins for the transcriptional activation of cdk inhibitor p21WAF1 gene. Further, the modulations 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 Carfilzomib prominent epigenetic marks that regulate the binding of different transcriptional factors.
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