Brief Mapping Report

Human Histone Deacetylase 2,HDAC2(HumanRPD3), Is Localized to 6q21 by Radiation Hybrid Mapping

Among post-translational modifications of proteins, acetylation, phosphorylation, and ubiquitination are most extensively studied over the last several decades. Owing to their different target residues for modifications, cross-talk between phosphorylation with that of acetylation and ubiquitination is relatively less pronounced. However, since canonical acetylation and ubiquitination happen only on the lysine residues, an overlap of the same lysine residue being targeted for both acetylation and ubiquitination happens quite frequently and thus plays key roles in overall functional regulation predominantly through modulation of protein stability. In this review, we discuss the cross-talk of acetylation and ubiquitination in the regulation of protein stability for the functional regulation of cellular processes with an emphasis on transcriptional regulation. Further, we emphasize our understanding of the functional regulation of Super Elongation Complex (SEC)-mediated transcription, through regulation of stabilization by acetylation, deacetylation and ubiquitination and associated enzymes and its implication in human diseases.

Acetylation and deacetylation of histone and several non-histone proteins are the two important processes amongst the different modes of epigenetic modulation that are involved in regulating cancer initiation and development. Abnormal expression of histone deacetylases (HDACs) is often reported in various types of cancers. Few pan HDAC inhibitors have been approved for use as therapeutic interventions for cancer treatment including vorinostat, belinostat and panobinostat. However, not all the HDAC isoforms are abnormally expressed in certain cancers, such as in the case of, ovarian cancer where overexpression of HDAC1-3, lung cancer where overexpression of HDAC 1 and 3 and gastric cancer where overexpression of HDAC2 is seen. Therefore, pan-inhibition of HDAC is not an efficient way to combat cancer via HDAC inhibition. Hence, isoform-selective HDAC inhibition can be one of the best therapeutic strategies in the treatment of cancer. In this context since aberrant expression of HDAC2 largely contributes to cancer progression by silencing pro-apoptotic protein expressions such as NOXA and APAF1 (caspase 9-activating proteins) and inactivation of tumor suppressor p53, HDAC2 specific inhibitors may help to develop not only the direct targets but also indirect targets that are crucial for tumor development. However, to develop a HDAC2 specific and potent inhibitor, extensive knowledge of its structure and specific functions is essential. The present review updates details on the structural features, physiological functions, and roles of HDAC2 in different types of cancer, emphasizing the challenges and status of the development of HDAC2 selective inhibitors against various types of cancer.

Freshwater planarians are flatworms of the Lophotrochozoan superphylum and are well known for their regenerative abilities, which rely on a large population of pluripotent adult stem cells. However, the mechanisms by which planarians maintain a precise population of adult stem cells while balancing proliferation and cell death, remain to be elucidated. Here we have identified, characterized, and functionally tested the core Retinoblastoma (Rb) pathway components in planarian adult stem cell biology. The Rb pathway is an ancient and conserved mechanism of proliferation control from plants to animals and is composed of three core components: an Rb protein, and a transcription factor heterodimer of E2F and DP proteins. Although the planarian genome contains all components of the Rb pathway, we found that they have undergone gene loss from the ancestral state, similar to other species in their phylum. The single Rb homolog (Smed-Rb) was highly expressed in planarian stem cells and was required for stem cell maintenance, similar to the Rb-homologs p107 and p130 in vertebrates. We show that planarians and their phylum have undergone the most severe reduction in E2F genes observed thus far, and the single remaining E2F was predicted to be a repressive-type E2F (Smed-E2F4-1). Knockdown of either Smed-E2F4-1 or its dimerization partner Dp (Smed-Dp) by RNAi resulted in temporary hyper-proliferation. Finally, we showed that known Rb-interacting genes in other systems, histone deacetylase 1 and cyclinD (Smed-HDAC1; Smed-cycD), were similar to Rb in expression and phenotypes when knocked down by RNAi, suggesting that these established interactions with Rb may also be conserved in planarians. Together, these results showed that planarians use the conserved components of the Rb tumor suppressor pathway to control proliferation and cell survival.

Since the identification of the first histone deacetylase (Taunton et al., Science 272, 408–411), several new members have been isolated. They can loosely be separated into entities on the basis of their similarity to various yeast histone deacetylases. The first class is represented by its closeness to the yeast Rpd3-like proteins, and the second most recently discovered class has similarities to yeast Hda1-like proteins. However, due to the fact that several different research groups isolated the Hda1-like histone deacetylases independently, there have been various different nomenclatures used to describe the various members, which can lead to confusion in the interpretation of this family's functions and interactions. With the discovery of another novel murine histone deacetylase, homologous to yeast Sir2, the number of members of this family is set to increase, as 7 human homologues of this gene have been isolated. In the light of these recent discoveries, we have examined the literature data and conducted a database analysis of the isolated histone deacetylases and potential candidates. The results obtained suggest that the number of histone deacetylases within the human genome may be as high as 17 and are discussed in relation to their homology to the yeast histone deacetylases.