Fig. 2

Effects of HDAC inhibitors in cancer cells. In healthy cells, promoters of TSGs are unmethylated and present an enrichment of active histone marks such as acetylation and methylation (e.g., H3K4, H3K79, H3R17), which are actively maintained by HATs and HMTs, respectively. Repressive histone marks (H3K9 and H3K27) are maintained unmethylated by specific HDMs. These chromatin marks promote the recruitment of co-activator complexes such as chromatin remodeling complex (e.g., SWI/SNF), transcription factors and RNA polymerase II, which in turn trigger transcription. In cancer cells, TSGs are transcriptionally silenced due to DNMT-mediated DNA hypermethylation, which allows the recruitment of MBDs that bind methyl CpG, which in turn promote the recruitment of repressive complexes (e.g., mSin3A or SMRT/N-CoR) and HDACs leading to histone hypoacetylation. Additionally, active histone methylation marks are removed by specific HDMs and replaced by repressive methylation marks (e.g., H3K9, H3K27, H3R2) by specific HMTs. These modifications promote chromatin condensation and block the recruitment of TF and RNA poly II complex. Consequently, inhibition of HDAC activities is responsible for the modulation of protein degradation, induction of cellular differentiation and apoptosis, and inhibition of telomerase expression and cell cycle progression. Bax Bcl-2-associated X protein, Bcl-2 B-cell lymphoma 2, CDK cyclin-dependent kinase, CDKN CDK inhibitor, DNMT DNA methyl transferase, HAT histone acetyl transferase, HDAC histone deacetylase, HDACi HDAC inhibitor, HIF hypoxia-inducible factor, HDM histone demethylase, HMT histone methyl transferase, hTERT human telomerase reverse transcriptase, MBD methyl binding domain protein, Pol II RNA polymerase II, RUNX runt-related transcription factor, Sin3 switch intensive 3, Smad7 mothers against decapentaplegic homolog 7, SMRT/N-CoR silencing mediator of retinoic acid and thyroid hormone receptors/nuclear hormone receptor co-repressor, SWI/SNF switch/sucrose non-Fermentable, TF transcription factor, TSG tumor suppressor gene