The Establishment Of Screening Models For Histone Deacetylase Inhibitors And Their Application In Screening Of The Chinese Traditional Medicine Effective Components

The regulation of gene expression is an essential process in the development ofeukaryotic organisms. Histone acetyltransferases (HATs) and histone deacetylases (HDACs)are emerging as important components of protein complexes that affect the dynamics ofchromatin folding during gene transcription. Histone acetylation levels are thought to resultfrom the equilibrium between competing acetyltransferases and deacetylases. Histoneacetylation is often associated with activated transcription and deacetylation correlates withtranscriptional repression. Histone deacetylase inhibitors (HDACi) are chemicals that restrainthe function of HDACs. Recent evidences suggested that HDACis play important roles indiverse cellular functions such as chromatin structure remodeling, gene silencing, cellproliferation, apoptosis and cellular signal transduction.The cyclin kinase inhibitor gene p21^WAF1/CIP1, originally described as a universal inhibitorof cyclin-dependent kinases, has since been shown to play a major role in cell apoptosis, celldifferentiation and cell-cycle withdrawal. As a critical oncogene, the expression ofp21^WAF1/CIP1 is associated with cancer;its down-regulation may lead to the development oftumors. The expression of p21^WAF1/CIP1 is obvious decreased in some cancers, such as breastcancer, colorectal cancer and ovarian cancer. Recent findings showed the HDAC inhibitors,such as TSA, NaB, PB, SAHA, FK-228, MS-275 and Oxamflatincan, may lead to p21^WAF1/CIP1activation, which is mainly found at the transcriptional level. Therefore, it is possible to utilizethe screening model containing p21^WAF1/CIP1 promoter reporter gene construct to screen theanticancer agents.In the present study, based on the fact that HDAC inhibitors induce the expression ofp21^WAF1/CIP1, we designed the p21^WAF1/CIP1 promoter reporter gene construct and established astably integrated cell line with this reporter construct. By using this cell line, we screenedHDAC inhibitors from a library of the Chinese traditional medicine effective components, andobtained one component containing the activity of HDACi. The result will contribute to thediscovery of HDAC inhibitors that can be potential new anticancer drugs based on theinhibition of histone deacetylases.