A Curcumin-Based CBP HAT Inhibitor Modulates the Transcription Functions of Tumor Suppressor p53

Coactivator CREB-binding protein (CBP) regulates the transcription program of p53, which orchestrates cellular responses to a wide-range of stress conditions that cause genomic instability. Given the ability of CBP to regulate transcription by multiple mechanisms, the biological significance of its acetylation-directed functions may not be fully clear. The present study demonstrates the development of a curcumin-derived modulator of CBP histone acetyl-transferase (HAT) activity, CM354, which inhibits acetylation of p53 on lysine 382, acetylation of histone H3K27 and autoacetylation of CBP. These epigenetic changes are concomitant with downregulation of p53 and CBP functions, which facilitate the presence of histone methyl transferase, Enhancer of zeste homolog 2 (EZH2), on CDKNI1A/p21 promoter, thereby, enhancing the level of trimethylation on H3K27. Treatment with CM354 results in the activation of PARP and the abrogation of cellular growth. Genome-wide network analysis depicts that CM354 could alter cell-fate by enrichment of chromatin H3K27 methylation and activation of the polycomb group of proteins. Though previously reported HAT inhibitors act at higher concentrations and lack cell permeability, the present study shows the impact of modulating endogenous CBP HAT activity on chromatin landscape and p53 functions. Gene expression in human U2OS cell lines after treatment of CM354 (1.5uM), Doxorubicin (300ng/ml), the combination of the two drugs, as well as the untreated control was measured. Each condition is performed in duplicates.