Disease relevance of HDAC4

• METHODS: Immunohistochemical staining of prostate sections of both benign tissue and primary and hormone relapsed prostate cancer, as well as of the CWR22 mouse xenograft model, and indirect quantitative immunofluorescence staining of endogenous HDAC4 in LNCaP cells [1].
• To study HDAC4 expression in benign prostatic hyperplasia, primary and hormone refractory (HR) CaP and to investigate the involvement of histone deacetylase activity in the development of the androgen insensitive phenotype [1].
• In lung carcinomas, HDAC4, KIAA0820 and Tip60 were downregulated (P < 0.01, P < 0.001 and P < 0.001 respectively) [2].
• CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy [3].
• To identify ERalpha N-terminal-specific coregulators, we screened a breast cDNA library by T7 phage display and isolated histone deacetylase 4 (HDAC4) [4].

High impact information on HDAC4

• Phosphorylation of HDAC4 by CaMKII promotes nuclear export and prevents nuclear import of HDAC4, with consequent derepression of HDAC target genes [3].
• In cardiomyocytes, CaMKII phosphorylation of HDAC4 results in hypertrophic growth, which can be blocked by a signal-resistant HDAC4 mutant [3].
• These findings reveal a central role for HDAC4 in CaMKII signaling pathways and have implications for the control of gene expression by calcium signaling in a variety of cell types [3].
• Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells [5].
• HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair [5].

Chemical compound and disease context of HDAC4

• Nuclear accumulation of histone deacetylase 4 (HDAC4) coincides with the loss of androgen sensitivity in hormone refractory cancer of the prostate [1].
• HD4, a 180 kDa polypeptide, which is one of the major constituents of the isolated HD fraction, has been suggested to be a glycoprotein, is probably identical to the 180 kDa bullous pemphigoid (BP) antigen [Owaribe, K., Nishizawa, Y., & Franke, W.W. (1991) Exp. Cell Res. 192, 622-630] [6].
• The K(d) values for Butyrivibrio fibrisolvens 49, Streptococcus bovis JB1, Clostridium aminophilum F, S. ruminantium HD4, and M. elsdenii B159 were 10, 65, 100, 1020, and 1330 nM monensin, respectively [7].

Biological context of HDAC4

• We show that HDAC4, unlike other deacetylases, shuttles between the nucleus and the cytoplasm in a process involving active nuclear export [8].
• In the nucleus, HDAC4 associates with the myocyte enhancer factor MEF2A [8].
• Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint [5].
• 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 [9].
• Histone deacetylase 4 (HDAC4) is a class II HDAC implicated in controlling gene expression important for diverse cellular functions, but little is known about how its expression and stability are regulated [10].

Anatomical context of HDAC4

• In the nucleus, the caspase-generated fragment of HDAC4 is able to trigger cytochrome c release from mitochondria and cell death in a caspase-9-dependent manner [11].
• In addition, endogenous HDAC4 and at least one of its binding partners, the corepressor protein SMRT (for silencing mediator of retinoid and thyroid receptor), undergo changes in their nuclear distribution in ICP0-transfected cells [12].
• Furthermore, the overexpression of HDAC4 inhibited cardiomyogenesis, shown by the downregulation of cardiac muscle gene expression [13].
• Here we show that HDAC4 is cytoplasmic during myoblast differentiation, but relocates to the nucleus once fusion has occurred [14].
• However, upon differentiation, this dynamic equilibrium is disturbed and we find that HDAC4 accumulates in the nuclei of myotubes, suggesting a positive role of nuclear HDAC4 in muscle differentiation [15].

Associations of HDAC4 with chemical compounds

• As for nuclear export, leucine-rich sequences located in the middle part of HDAC4 do not function as nuclear export signals [16].
• Of two potential caspase consensus motifs in HDAC4, both lying within a region containing proline-, glutamic acid-, serine-, and threonine-rich (PEST) sequences, we identified, by site-directed mutagenesis, Asp-289 as the prime cleavage site [10].
• Cleavage of HDAC4 occurs at Asp 289 and disjoins the carboxy-terminal fragment, localized into the cytoplasm, from the amino-terminal fragment, which accumulates into the nucleus [11].
• Here we report that serine/threonine kinases are found in association with HDAC4 and phosphorylate HDAC4 in vitro, and HDAC4 is phosphorylated in cells [17].
• Moreover, we have found that HDAC4 interacts with the 14-3-3 family of proteins that are known to bind specifically to conserved phosphoserine-containing motifs [18].

Physical interactions of HDAC4

• These results suggest that HDAC4 interacts with transcription factors such as MEF2C to negatively regulate gene expression [19].
• We report that HDAC4 and MITR contain calmodulin-binding domains that overlap with their MEF2-binding domains [20].

Regulatory relationships of HDAC4

• The results from transient transfection and co-precipitation experiments suggest that 14-3-3tau activates MEF2D by competitively inhibiting HDAC4 from binding to MEF2D and thereby affects muscle cell differentiation [21].
• Removal of amino acids 166-289 from the caspase-cleaved fragment of HDAC4 abrogates its ability to repress MEF2 transcription and to induce cell death [11].
• HDAC9 is expressed in a tissue-specific pattern that partially overlaps that of HDAC4 [22].
• Furthermore, Parkin controls the intracellular levels of sumoylated HDAC4, as a result of the ubiquitination and degradation of RanBP2 [23].

Other interactions of HDAC4

• HDAC4 and HDAC5 contain a noncatalytic N-terminal domain [9].
• The nuclear localization domain of the MEF2 family of transcription factors shows member-specific features and mediates the nuclear import of histone deacetylase 4 [24].
• HDAC1 and 3 siRNA produced a concentration-dependent inhibition of HeLa cell proliferation; whereas, HDAC4 and 7 siRNA showed no effect [25].
• The caspase-cleaved amino-terminal fragment of HDAC4 acts as a strong repressor of the transcription factor MEF2C, independently from the HDAC domain [11].
• In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit [26].

Analytical, diagnostic and therapeutic context of HDAC4

• To characterize the cellular function of the recently identified HDAC4 and HDAC5 proteins, complexes were isolated by immunoprecipitation [27].
• Western blotting also showed that HDAC1 and HDAC4 protein levels were 1.21-and 1.48-fold higher, respectively, in muscle from torpid animals [28].
• Assignment of the human histone deacetylase 4 gene (HDAC4) to chromosome 2q37.2 by in situ hybridization [29].
• 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 [30].
• Patients with risk factors or in stage IIIA received chemo radiotherapy (CMT; trial HD5); others received extended field radiotherapy (RT) alone (HD4) [31].

References