Disease relevance of HDAC6

• Finally, we evaluated HDAC6 protein expression in 139 consecutively archived human breast cancer tissues by immunohistochemical staining [1].
• These results demonstrate that HDAC6 plays a significant role in regulating HIV-1 infection and Env-mediated syncytia formation [2].
• We investigated the expression levels of HDAC6 mRNA and protein expression in oral squamous cell carcinoma (OSCC)-derived cell lines and human primary OSCCs to elucidate the potential involvement of HDAC6 in OSCC [3].
• Histone deacetylase 6 regulates human immunodeficiency virus type 1 infection [2].
• A total of 266 patients with advanced HD treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD) were analyzed (HD6 trial of the German Hodgkin's Lymphoma Study Group) [4].
• Pharmacologic inhibition of HDAC6 also reduces ovarian cancer cell spreading and migration consistent with its known function in regulating microtubule polymerization via deacetylation of alpha-tubulin [5].

Psychiatry related information on HDAC6

• Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation [6].

High impact information on HDAC6

• The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress [7].
• Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription [8].
• Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility [8].
• Overexpression of HDAC6 but not a dead deacetylase mutant in T cells disorganized CD3 and LFA-1 at the immune synapse [9].
• HDAC6 deacetylase activity links the tubulin cytoskeleton with immune synapse organization [9].

Chemical compound and disease context of HDAC6

• Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer [1].

Biological context of HDAC6

• Interestingly, HDAC6 contains an internal duplication of two catalytic domains, which appear to function independently of each other [10].
• Although the PAZ domain possesses homology with the zinc finger of deubiquitinating enzymes, it is dispensable for the deubiquitinating activity we find associated with HDAC6 following immunopurification [11].
• Virus replication is enhanced in HDAC6-depleted cells, demonstrating HDAC6 is an essential component of innate antiviral immunity [12].
• Trapoxin B, a weak HDAC6 inhibitor, and calyculin A, a cell-permeable phosphatase inhibitor, had no effect on the stability of the HDAC6.PP1 complexes or on tubulin acetylation [13].
• Cell motility was increased to the same degree by stably transfecting the HDAC6 expression vector into MCF-7 cells [1].

Anatomical context of HDAC6

• HDAC6 also colocalized and coimmunoprecipitated with the nuclear matrix-associated protein Runx2 in osteoblasts [14].
• HDAC6 overexpression disrupted the localization of p58, a protein that mediates binding of Golgi elements to microtubules [15].
• We show that ATG proteins, molecular determinants of autophagic vacuole formation, and lysosomes are recruited to pericentriolar cytoplasmic inclusion bodies by a process requiring an intact microtubule cytoskeleton and the cytoplasmic deacetylase HDAC6 [16].
• Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells [17].
• By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathologic factors, namely, age, menopausal status, and axillary lymph node involvement [17].

Associations of HDAC6 with chemical compounds

• HDAC6, which is insensitive to trapoxin B, specifically interacted with the carboxy terminus of Runx2 [14].
• PP1 binding was mapped to the second catalytic domain and adjacent C-terminal sequences in HDAC6, and treatment of cells with trichostatin A (TSA) disrupted endogenous HDAC6.PP1 complexes [13].
• These results indicate the biological significance of HDAC6 regulation via estrogen signaling [1].
• Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered [6].
• To prove this hypothesis, we used bortezomib and tubacin to inhibit the proteasome and HDAC6, respectively [18].

Physical interactions of HDAC6

• Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone association of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl [19].

Co-localisations of HDAC6

• SIRT2 colocalizes and interacts in vivo with HDAC6, another tubulin deacetylase [20].

Regulatory relationships of HDAC6

• Either the selective estrogen receptor modulator tamoxifen (TAM) or the pure antiestrogen ICI 182,780 prevented estradiol-induced HDAC6 accumulation and deacetylation of alpha-tubulin, leading to reduced cell motility [1].
• TGF alpha induced a 2-fold increase in growth of the HD8 subline but inhibited the growth of the more differentiated HD6 subline by 40% [21].
• We showed that TGF-beta1-induced EMT is accompanied by HDAC6-dependent deacetylation of alpha-tubulin [22].

Other interactions of HDAC6

• HDAC10 was classified as a class II subfamily member based upon similarity to HDAC6 [23].
• In vitro biochemical studies showed that recombinant HDAC6, but not HDAC4, bound directly to the protein phosphatase (PP)1 catalytic subunit [13].
• Complexes shown to contain HDAC1, HDAC3, HDAC6, and HDAC1+2 as their catalytic subunits have been used in an antibody-based assay that detects deacetylation of whole histones at defined lysines [24].
• Both HDAC6 and HDAC9 possess unique structural modules, so they may have special biological functions [25].
• Only SIRT1 was consistently overexpressed (>2 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells [26].

Analytical, diagnostic and therapeutic context of HDAC6

• Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival [17].
• HDAC6 protein expression was also determined by immunohistochemistry [17].
• HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated [17].
• Fluorescence in situ hybridization analysis localized the human HDAC6 gene to the subband border of chromosome Xp11.22-23, a region which is characterized by frequent gains and losses of chromosomal material in several types of cancer and neurological disorders [27].
• Confocal videomicroscopy studies revealed that the HDAC6 tubulin deacetylase was translocated and concentrated at the contact site of T cells with APCs [9].

References