The Screening And Primary Functional Study Of Histone Deacetylase Inhibitors From Polyoxometallates

The reguLation of gene expression is an essential process in the development of eukaryotic organisms. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are emerging as important components of protein complexes that affect the dynamics of chromatin folding during gene transcription. Histone acetylation levels are thought to resuLt from the equilibrium between competing acetyltransferases and deacetylases. Histone acetylation is often associated with activated transcription and deacetylation correlates with transcriptional repression. Histone deacetylase inhibitors (HDACIs) are chemicals that restrain the function of HDACs. Recent evidences suggested that HDACIs play important roles in diverse celluLar functions such as chromatin structure remodeling, gene silencing, cell proliferation, apoptosis and celluLar signal transduction.The cyclin kinase inhibitor gene p21~WAF1/CIP1), originally described as a universal inhibitor of cyclin-dependent kinases, has since been shown to play a major role in cell apoptosis, cell differentiation and cell-cycle withdrawal. As a critical oncogene, the expression of p21~WAF1/CIP1) is associated with cancer; its down-reguLation may lead to the development of tumors. The expression of p21~WAF1/CIP1) is obvious decreased in some cancers, such as breast cancer, colorectal cancer and ovarian cancer. Recent findings showed the HDAC inhibitors, such as TSA, BUA, PB, SAHA, FK-228, MS-275 and Oxamflatincan, may lead to p21~WAF1/CIP1)activation, which is mainly found at the transcriptional level. Therefore, it is possible to utilize the screening model containing p21~WAF1/CIP1) promoter reporter gene construct to screen the anticancer agents.Polyoxometallates (POMs) are early transition metal oxygen anion clusters, which are oligomeric aggregates of metal cations (usually the d0 species) bridged by oxide anions that form by self-assembly processes as discrete metal-oxide cluster anions. Isopolyanions are polyanions assembled by the same oxyacid ions, heteropolyanions are assembled by the different oxyacid ions. POMs have been widely recognized that this class of metal-oxygen cluster species exhibits a unique variety of structures, electrochemistry and properties that make them usefuL studied and applied in medicine. Several lines of evidence using different techniques and types of experiments indicate that POMs do, in fact, cross cell membranes and come into the cells. That is usefuL for screening the histone deacetylase inhibitor.Thirteen new histone deacetylase inhibitors (HDACI)-like compounds have been detected from 400 polyoxometallates (POMs) using the p21~WAF1/CIP1) promoter reporter system established by our lab previously. PA-320 inhibits proliferation of various cancer cells including HeLa,A549,293T,LNcaP and SW620 in MTT assay, with IC50 value is 38-70 ug/mL. Furthermore, PA-320 can enhance the activity of p21~WAF1/CIP1) promoter and repress function of HDAC1 obviously. PA-320 can induce p21 mRNA transcription, too. Conclusion: comparing to the well-known HDAC inhibitor TSA, PA-320 has the same activity trend as TSA. Our research highlights therapy of cancer using POMs.