Disease relevance of HDAC9

• In this study, the antitumor effects of SK-7041, one of those novel HDAC inhibitors, was evaluated on lung and breast cancer cell lines [1].
• We recently reported on a novel mechanism of chemoprotection by SFN in human colon cancer cells and prostate epithelial cells, namely the inhibition of histone deacetylase (HDAC) [2].
• In this study, we have investigated the HbF-inducing activity and molecular mechanisms of specific histone deacetylase (HDAC) inhibitors in human K562 erythroleukemia cells [3].
• Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells [4].
• Epigenetic alterations of chromatin due to aberrant histone deacetylase (HDAC) activity and transcriptional silencing of all-trans retinoic acid (ATRA) pathway are events linked to the pathogenesis of acute myeloid leukemia (AML) that can be targeted by specific treatments [5].

High impact information on HDAC9

• We show that histone deacetylase 7 (HDAC7) is specifically expressed in the vascular endothelium during early embryogenesis, where it maintains vascular integrity by repressing the expression of matrix metalloproteinase (MMP) 10, a secreted endoproteinase that degrades the extracellular matrix [6].
• Disruption of the HDAC7 gene in mice results in embryonic lethality due to a failure in endothelial cell-cell adhesion and consequent dilatation and rupture of blood vessels [6].
• We present evidence that Rb forms a repressor containing histone deacetylase (HDAC) and the hSWI/SNF nucleosome remodeling complex, which inhibits transcription of genes for cyclins E and A and arrests cells in the G1 phase of the cell cycle [7].
• Myosin phosphatase dephosphorylates HDAC7, controls its nucleocytoplasmic shuttling, and inhibits apoptosis in thymocytes [8].
• After T-cell receptor (TCR) activation, the serine/threonine kinase PKD1 phosphorylates HDAC7, resulting in its nuclear export and the derepression of its target genes [8].

Chemical compound and disease context of HDAC9

• The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis, but displays no toxicity in endothelial cells [9].
• Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo [10].
• To investigate whether chromatin structure controls glial cell-specific expression of JC virus early genes, glial and nonglial cells were transfected with a reporter plasmid containing the JC virus early promoter and then treated with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate [11].
• PURPOSE: To assess the antitumor effects of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, (S)-HDAC-42, vis-à-vis suberoylanilide hydroxamic acid (SAHA) in in vitro and in vivo models of human prostate cancer [12].
• EXPERIMENTAL DESIGN: We examined the effects of a HDAC inhibitor, depsipeptide, on the growth of chondrosarcoma cell lines [13].

Biological context of HDAC9

• HDAC9 and HDAC9a contain the HDAC catalytic domain, and Flag-tagged HDAC9 and HDAC9a possess deacetylase activity [14].
• Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation [15].
• These results suggest that HDAC9 plays a role in hematopoiesis; its deregulated expression may be associated with some human cancers [16].
• Inappropriate or inadequate TGFbeta2 expression, together with deficient mediation of these signals at the transcription level, due to an altered HDAC9 isoforms ratio, may also lead to the observed ocular phenotype [17].
• A candidate gene from each breakpoint was identified: on chromosome 7, histone deacetylase 9 (HDAC9), disrupted by the translocation breakpoint, and on chromosome 1, transforming growth factor-beta2 (TGFbeta2) located 500 kb proximal to the breakpoint [17].

Anatomical context of HDAC9

• Similar to histone deacetylase-related protein, HDAC9 transcripts are expressed at high levels in brain and skeletal muscle [14].
• HDAC9 and HDAC9a also repress myocyte enhancer-binding factor 2-mediated transcription [14].
• Within the human hematopoietic system, expression of HDAC9 is biased toward cells of monocytic and lymphoid lineages [16].
• Interestingly, in HeLa cells, HDAC7 was predominantly nuclear [18].
• Inhibition of HDAC increases Runx2 acetylation, and potentiates BMP-2-stimulated osteoblast differentiation and increases bone formation [19].

Associations of HDAC9 with chemical compounds

• We find that Gam1 expression increases the level of transcription from a variety of eukaryotic promoters, similar to the effect of treating cells with the histone deacetylase (HDAC) inhibitor trichostatin A (TSA ) [20].
• Background and purpose:The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent [21].
• BACKGROUND: A class of synthetic histone deacetylase (HDAC) inhibitors, which are hybrids of trichostatin A and MS-275 were previously developed [1].
• We investigated the induction of the human fetal globin gene using five potent histone deacetylase (HDAC) inhibitors: FK-228, HC-Toxin, Trichostatin, MS-275, and Apicidin, using in vitro assays and cultures of primary human erythroblasts [22].
• Sulforaphane retards the growth of human PC-3 xenografts and inhibits HDAC activity in human subjects [2].

Physical interactions of HDAC9

• HDRP also interacts with histone deacetylase 1 (HDAC1) and recruits it to the c-Jun gene promoter, resulting in an inhibition of histone H3 acetylation at the c-Jun promoter [23].

Regulatory relationships of HDAC9

• MEF2-interacting transcription repressor (MITR) is an amino-terminal splice variant of HDAC9 that also potently inhibits MEF2 transcriptional activity despite lacking a catalytic domain [24].
• HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4 [16].
• HDAC7 inhibits Nur77 expression, an orphan receptor involved in antigen-induced cell death and in negative selection [25].

Other interactions of HDAC9

• Herein, we report the identification of a protein HDRP (HDAC-related protein) that shares 50% identity in deduced amino acid sequence to the noncatalytic N-terminal domain of HDAC4 and 5 [26].
• The data also suggest that the promoter bound MEF2 is potentially capable of remodeling adjacent nucleosomes via the recruitment of HDAC7 [18].
• Consequently, we show that ICP0 is able to overcome the HDAC5 amino-terminal- and MITR-induced MEF2A repression in gene reporter assays [27].
• Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions [28].
• During T cell receptor activation, HDAC7 is exported from the nucleus leading to the derepression of Nur77 expression and the induction of apoptosis [25].

Analytical, diagnostic and therapeutic context of HDAC9

• Although only the HDAC9 gene is disrupted by the breakpoint, we consider that TGFbeta2 represents the main candidate gene in this family, which is elicited in mice by the Tgfbeta2-null status and by the TGFbeta2-induced cataractus changes in animal models [17].
• Fluorescence in situ hybridization analysis localized the human HDAC9 gene to chromosome 7p21, a region which has been associated particularly with the pathogenesis of gynecological tumors [29].
• Hydroxamic acid (HA)-based histone deacetylase (HDAC) inhibitors, with trichostatin A (TSA) as the reference compound, are potential antitumoral drugs and show promise in the creation of long-term primary cell cultures [30].
• Based on the Western blot analysis, this HDAC inhibitory effect of IN-2001 was confirmed by an increase in histone H4 acetylation from the IN-2001-treated breast cancer cells [31].
• PATIENTS AND METHODS: This analysis comprises 4,626 HL patients of all prognostic risk groups who were enrolled onto the multicenter studies HD4 to HD9 of the German Hodgkin Study Group. At 5.5 years, 2,050 female and 2,576 male patients were analyzed [32].

References