ctivity P-glycoprotein of compounds such as the spiruchostatins A and B , diheteropeptin , scriptaid, and A 161906 were all discovered using these assays and subsequently, the mechanism of action of all these compounds was determined to be inhibition of HDACs. These observations emphasize the prominent role of HDACs in the signaling pathways regulated by TGFb and how modulation of chromatin structure can produce desired pharmacological effects. 1.1. Deacetylase enzymes—the HDAC family The HDACs can be divided into two families, the Zn+2 dependent HDACfamily composed of class I , class II a/b , and class IV and Zn+2 independent NAD dependent class III SIRT enzymes . The class I HDACs, apparently the truehistone deacetylases, are localized to the nucleus of cells.
The classes II a/b deacetylases have both histones and non histone proteins as substrates and are primarily localized to the cytoplasm but are known to shuttle in and out of the nucleus through association with 14 3 3 proteins. The class II enzymes are characterized by either a large N terminal domain or a second catalytic domain . The class III SIRTs are NAD+ Sorafenib dependent deacetylases with non histone proteins as substrates and have been linked to regulation of caloric utilization of cells . HDACs do not function independently but rather in concert with multi protein complexes that are recruited to specific regions of the genome that in turn generate the unique spectrum of expressed and silenced genes that are characteristic of the expression profile responsible for the malignant phenotype of cancer cells.
One key question relates to which of the HDAC are important to inhibit to obtain the desired pharmacological profile for the therapy of cancer. Genetic studies, knockout in yeast and siRNA in mammalian cells, have indicated that the class I HDACs are essential to cell proliferation and survival . However, few studies dermatology have addressed the in vitro HDAC enzyme selectivity of low molecular weight HDAC inhibitors between classes I and II HDACs, most likely due to the difficulty in obtaining isolated isozymes free of other HDACs . As described above, the HDACs function in complexes with other co repressor proteins and in concert with DNA and histone methylation; therefore, one should exercise caution in the strict interpretation of results with siRNA knockdown or any other type of genetic knockdown/knockout that eliminates these proteins entirely from the complex and may therefore have effects other than those observed when using small molecule inhibitors.
Minucci and Pelicci state . no conclusive experimental evidence that points to specific HDACs as being selectively involved in any form of disease, including cancer.However, experiments have demonstrated that HDAC1 knockout is embryonic lethal, HDAC2 knockdown by siRNA regulates cell survival , and that siRNA knockdown of HDACs 1 and 3 but not 4 and 7 results in an antiproliferative phenotype . All these data suggest the role of class I HDACs in cancer cell proliferation and survival and that dysregulation of their normal function is potentially a driving force in neoplastic transformation and progression. So exactly how do HDACIs cause cancer cell death? As with most pharmacological agents, the type of cell death induced by HDACIs can.