By preventing the interaction of pro-apoptotic proteins with mitochondria the bound enzyme acts essentially as an anti-apoptotic agent. Indeed, it has been shown that the release of apoptotic proteins such as cytochrome c depends on the integrity of the Nterminal portion of VDAC. Since it was demonstrated that HK and Bcl-2 were able to confer protection against apoptosis through interaction with the VDAC 1 N-terminal region, the participation of HK II as a promoter of cell differentiation was strengthened. Enzymes of the glycolytic and oxidative pathways are, as proteins in general, amenable to regulation of gene expression at the level of chromatin. Chromatin structures alternate between compacted and relaxed conformations which in turn depend on acetylation and deacetylation of the histone protein core. The enzymatic systems involved in these processes are histones acetyl transferases that add acetyl groups to lysine residues and histone deacetylases that remove them. Compacted and relaxed chromatins have been linked to gene expression repression and activation, respectively. Although histones constitute the prime substrates for HATs and HDCAs, other non-histone proteins such as transcriptional factors-p53, pRb retinoblastoma protein and HIF-1a; chaperones, metabolic enzymes and steroid receptors are also acetylated/deacetylated by these enzymes. Therefore, HATs and HDACs can affect a broad spectrum of biological processes that include growth arrest, DNA repair, cellular bioenergetics, cell death pathways, mitosis, generation of reactive oxygen species, senescence and angiogenesis. Because of its VE-822 1232416-25-9 repressive actions, HDACs have become interesting targets for the development of drugs that could retrieve the ability of transformed cells to undergo apoptosis. Currently, several HDAC inhibitors LY2157299 obtained from natural or synthetic sources have been characterized. They are grouped into five chemical classes which include hydroxamic acid and derived compounds, benzamides, cyclic peptides, short chain fatty acids and ketones. As mentioned above, the HDACis change several functions in normal and transformed cells which makes it difficult to pinpoint a mechanism of action to these drugs. Several reports exist showing the action of HDACi on the cell cycle and apoptosis. The present work has dissected these broad actions by focusing on the energy metabolism and demonstrating that HDACis can affect proliferation by acting on individual enzymes of the glycolytic and oxidative pathways. The information available so far studying mitochondria from rat liver treated with the short chain fatty acid derivative valproate have shown that it inhibits fatty acid boxidation and in general depresses cell oxidative metabolism leading to a decrease in both, the rate of O2 consumption coupled to ATP synthesis and cytochrome oxidase activity. Colorectal adenocarcinomas cells treated with butyrate, another short chain fatty acid class HDACi, inhibited glucose uptake and oxidation, as well as ribose synthesis and increased de novo fatty acid synthesis along with activation of the PPP. However MIA cells, butyrate-resistant pancreatic adenocarcinoma, did not display any changes in their metabolic profile after treatment. These metabolic changes were correlated to induction of differentiation processes mediated by butyrate and consequently with its inhibitory effects on growth. Similar results were obtained with cells exposed to TSA. In myeloma cells, the HDACis VPA and suberoylanilide hydroxamic acid induced a decrease in glucose uptake, GLUT 1 expression and HK activity, leading to apoptosis in tumor cells.