| 2021 | Understanding the role of histone deacetylase and their inhibitors in neurodegenerative disorders: Current targets and future perspective. | Curr Neuropharmacol | Neurodegenerative diseases are the group of pathological conditions that cause motor inc-ordination (jerking movements), cognitive and memory impairments result due to degeneration of neurons in a specific area of the brain. Oxidative stress, mitochondrial dysfunction, excitotoxicity, neuroinflammation, neurochemical imbalance and histone deacetylase enzymes (HDAC) are known to play a crucial role in neurodegeneration. HDAC is classified into four categories (class I, II, III and class IV) depending upon their location and functions. HDAC1 and 2 are involved in neurodegeneration while HDAC3-11 and class III HDACs are beneficial as neuroprotective. HDACs are localized in different parts of the brain- HDAC1 (hippocampus and cortex), HDAC2 (nucleus), HDAC3, 4, 5, 7 and 9 (nucleus and cytoplasm), HDAC6 & HDAC7 (cytoplasm) and HDAC11 (Nucleus, Cornus ammonis 1 and spinal cord). In pathological conditions, HDAC up-regulates glutamate, phosphorylation of tau, and glial fibrillary acidic proteins while down-regulates BDNF, Heat shock protein 70, Gelsolin. Class III HDACs are divided into seven sub-classes (SIRT1-SIRT7). Sirtuins are localized in the different parts of the brain and neuron -Sirt1 (nucleus), Sirt2 (cortex, striatum, hippocampus and spinal cord), Sirt3 (mitochondria and cytoplasm), Sirt4, Sirt5 & Sirt6 (mitochondria), Sirt7 (nucleus) and Sirt8 (nucleolus). SIRTs (1, 3, 4, and 6) are involved in neuronal survival, proliferation and modulating stress response, and SIRT2 is associated with Parkinsonism, Huntington disease and Alzheimer's disease, whereas, SIRT6 is only associated with Alzheimer's disease. In this critical review, we have discussed the mechanisms and therapeutic targets of HDACs would be beneficial for the management of neurodegenerative disorders. |
| 2020 | In Vitro Maturation with Leukemia Inhibitory Factor Prior to the Vitrification of Bovine Oocytes Improves Their Embryo Developmental Potential and Gene Expression in Oocytes and Embryos. | Int J Mol Sci | Oocyte cryopreservation has a significant impact on subsequent embryonic development. Herein, we investigated whether supplementing in vitro maturation medium with Leukemia Inhibitory Factor (LIF) prior to vitrification affects embryo development and gene expression at different embryo developmental stages. A panel of genes including maternal effect, epigenetics, apoptosis and heat stress was relatively quantified. The results show reduced cleavage rates after vitrification, regardless of the LIF treatment. Although not statistically different from control-vitrified oocytes, oocyte apoptosis and the blastocyst yield of LIF-vitrified oocytes were similar to their non-vitrified counterparts. Vitrification increased oocyte , and gene expression while its expression decreased in LIF-vitrified oocytes to similar or close levels to those of non-vitrified oocytes. With a few gene-specific exceptions, vitrification significantly increased the expression of , , , and in oocytes and most stages of embryo development, while comparable expression patterns for these genes were observed between LIF-vitrified and non-vitrified groups. Vitrification increased expression in oocytes and in 2-cell embryos. Our data suggest that vitrification triggers stage-specific changes in gene expression throughout embryonic development. However, the inclusion of LIF in the IVM medium prior to vitrification stimulates blastocyst development and several other developmental parameters and induces oocytes and embryos to demonstrate gene expression patterns similar to those derived from non-vitrified oocytes. |
| 2020 | Design of Dual Inhibitors of Histone Deacetylase 6 and Heat Shock Protein 90. | ACS Omega | Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are widely investigated anticancer drug targets. Importantly, several lines of evidence indicate that their regulation and activity are intimately linked, and that their combined inhibition may lead to impressive therapeutic benefits. In this study, we developed and applied an integrated computational strategy to design dual inhibitors of HDAC6 and Hsp90. Although the two targets share very little homology, an integrated ligand-based and structure-based virtual screening approach indicated a subset of compounds possessing the key structural requirements for binding at both targets. tests demonstrated that some of the selected candidates are able to selectively inhibit HDAC6 over HDAC1, to increase the acetylation levels of tubulin on cell assays and to reduce cell proliferation. The discovered compounds represent valuable starting points for further hit optimization. |
| 2020 | Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models. | Cell Stress Chaperones | Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol. |
| 2019 | CFP-1 interacts with HDAC1/2 complexes in C. elegans development. | FEBS J | CXXC finger binding protein 1 (CFP-1) is an evolutionarily conserved protein that binds to non-methylated CpG-rich promoters in mammals and Caenorhabditis elegans. This conserved epigenetic regulator is part of the COMPASS complex that contains the H3K4me3 methyltransferase SET1 in mammals and SET-2 in C. elegans. Previous studies have indicated the importance of CFP1 in embryonic stem cell differentiation and cell fate specification. However, neither the function nor the mechanism of action of CFP1 is well understood at the organismal level. Here, we have used cfp-1(tm6369) and set-2(bn129) C. elegans mutants to investigate the function of CFP-1 in gene induction and development. We have characterised C. elegansCOMPASS mutants cfp-1(tm6369) and set-2(bn129) and found that both cfp-1 and set-2 play an important role in the regulation of fertility and development of the organism. Furthermore, we found that both cfp-1 and set-2 are required for H3K4 trimethylation and play a repressive role in the expression of heat shock and salt-inducible genes. Interestingly, we found that cfp-1 but not set-2 genetically interacts with histone deacetylase (HDAC1/2) complexes to regulate fertility, suggesting a function of CFP-1 outside of the COMPASS complex. Additionally, we found that cfp-1 and set-2 independently regulate fertility and development of the organism. Our results suggest that CFP-1 genetically interacts with HDAC1/2 complexes to regulate fertility, independent of its function within the COMPASS complex. We propose that CFP-1 could cooperate with the COMPASS complex and/or HDAC1/2 in a context-dependent manner. |
| 2018 | [Validation and Evaluation of Diagnostic Efficiency of Genes Associated with Colorectal Cancer with Hyperglycemia]. | Zhongguo Yi Xue Ke Xue Yuan Xue Bao | Objective To verify the expressions of genes associated with colorectal cancer with hyperglycemia and evaluate their diagnostic values.Methods Tumor tissues,distal normal intestinal mucosa,and peripheral blood samples were harvested from 109 colorectal cancer patients and peripheral blood samples from 30 diabetes patients and 30 healthy volunteers. The mRNA expressions of glucose regulated protein 78 (GRP78),NADPH oxidase-1 (NOX1),carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5),heat shock protein 60 (HSP60),and histone deacetylase 1(HDAC1) were detected by real-time quantitative polymerase chain reaction. The correlation between the gene expressions and clinicopathological parameters in colorectal cancer patients were analyzed using Pearson's correlation analysis. Diagnostic test accuracy evaluation was used to calculate the sensitivity,specificity,accuracy,predictability,Youden index,and likelihood ratio of serum gene expressions in colorectal cancer patients,and the receiver operating characteristic (ROC) curves were drawn. The area under the ROC curve was calculated to evaluate the diagnostic efficiency of the combined detection of multiple genes.Results The mRNA levels of GRP78 (P=0.001),NOX1 (P=0.022),CEACAM5 (P=0.000),HSP60 (P=0.044),and HDAC1 (P=0.047) were positively correlated with the fasting blood glucose level. The mRNA expressions of NOX1 (P=0.000,P=0.008) and HDAC1 (P=0.000,P=0.037) in tissues and serum were significantly higher in colorectal cancer patients than in patients with normal blood glucose levels. The NOX1 mRNA expression was positively correlated with the diameter of colorectal cancer (P=0.013),and the HDAC1 mRNA expression was significantly correlated with the tumor site (P=0.049),depth of primary tumor invasion (P=0.025),and TNM stage (P=0.042). The areas under the ROC curves of NOX1,CEACAM5,and HDAC1 were 0.931,0.852,and 0.860 respectively (all P=0.000). The specificity,accuracy,and negative predictive value of NOX1,HDAC1 mRNA expression in colorectal cancer patients with hyperglycemia were all above 90%. The diagnostic sensitivity and specificity of the combined detection of NOX1,CEACAM5,and HDAC1 were 98.82% and 99.93%,respectively.Conclusion Combined detection of genes associated with colorectal cancer accompanied by hyperglycemia can improve the diagnostic efficiency of early screening. |
| 2019 | Epigenetics and the vaginal microbiome: influence of the microbiota on the histone deacetylase level in vaginal epithelial cells from pregnant women. | Minerva Ginecol | Histone deacetylase (HDAC) influences the acetylation status of histones at gene promotor loci, providing an epigenetic mechanism that regulates gene expression.We determined if variations in the composition of the vaginal microbiome in pregnant women were associated with alterations in the level of HDAC1 in vaginal epithelial cells and whether this influenced the concentration of compounds present in vaginal fluid. Vaginal epithelial cells were obtained from 150 women in their first trimester of pregnancy, lysed and assayed for HDAC1 by ELISA. Composition of the vaginal microbiome was determined by classification of sequences amplified from the V1-V3 region of bacterial ribosomal 16S rRNA genes. Vaginal secretions were assayed for total protein, matrix metalloproteinase (MMP)-8, the 70kDa heat shock protein (hsp70) and the D- and L-lactic acid isomers.Lactobacilli were numerically dominant in 119 (79.3%) of the women, with Lactobacillus crispatus being the most prevalent (45.3% of women). Gardnerella was the most prevalent non-Lactobacillus species (10.7% of women). The median HDAC1 level in epithelial cells was 6.1 ng/mL when lactobacilli predominated vs. 20.5 ng/mL when non-lactobacilli were dominant (P=0.0039). Levels were lowest when L. crispatus was dominant (3.8 ng/mL) and highest with Streptococcus dominance (38.1 ng/mL). The concentration of HDAC1 was negatively correlated with the D-lactic acid level (P=0.0183) and positively correlated with concentrations of MMP-8 and hsp70 (P<0.0001) in the vaginal fluid.We propose that the composition of the vaginal microbiome and level of D-lactic acid, by influencing the HDAC1 level in vaginal epithelial cells, may epigenetically contribute to variations in the concentration of compounds in vaginal fluid. |
| 2019 | Insights into structural features of HDAC1 and its selectivity inhibition elucidated by Molecular dynamic simulation and Molecular Docking. | J Biomol Struct Dyn | Histone deacetylases (HDACs) are a family of proteins whose main function is the removal of acetyl groups from lysine residues located on histone and non-histone substrates, which regulates gene transcription and other activities in cells. HDAC1 dysfunction has been implicated in cancer development and progression; thus, its inhibition has emerged as a new therapeutic strategy. Two additional metal binding sites (Site 1 and Site 2) in HDACs have been described that are primarily occupied by potassium ions, suggesting a possible structural role that affects HDAC activity. In this work, we explored the structural role of potassium ions in Site 1 and Site 2 and how they affect the interactions of compounds with high affinities for HDAC1 (AC1OCG0B, Chlamydocin, Dacinostat and Quisinostat) and SAHA (a pan-inhibitor) using molecular docking and molecular dynamics (MD) simulations in concert with a Molecular-Mechanics-Generalized-Born-Surface-Area (MMGBSA) approach. Four models were generated: one with a potassium ion (K) in both sites (HDAC1), a second with K only at site 1 (HDAC1), a third with K only at site 2 (HDAC1) and a fourth with no K (HDAC1). We found that the presence or absence of K not only impacted the structural flexibility of HDAC1, but also its molecular recognition, consistent with experimental findings. These results could therefore be useful for further structure-based drug design studies addressing new HDAC1 inhibitors. |
| 2018 | Anti-inflammatory effect of lovastatin is mediated via the modulation of NF-κB and inhibition of HDAC1 and the PI3K/Akt/mTOR pathway in RAW264.7 macrophages. | Int J Mol Med | Lovastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor that is clinically used for the prevention of cardiovascular diseases. Although it has been reported that lovastatin has anti-inflammatory properties in several studies, how lovastatin regulates the inflammation is still unclear. To evaluate the effect of lovastatin on nitric oxide production (NO) in RAW264.7 macrophages, NO production assay was performed. Also, cell viability was measured to confirm cytotoxicity. Level of tumor necrosis factor-α (TNF-α) transcription was measured by reverse transcription polymerase chain reaction (RT-PCR) from total RNA in RAW264.7 cells. Western blot analysis and immunofluorescence staining were used to investigate the regulation of lovastatin on the expression, phosphorylation, and nuclear translocation of cellular proteins. The results of the present study revealed that lovastatin reduced nitric oxide production via the reduction of inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. The mRNA level of TNF-α was reduced in presence of lovastatin. In addition, lovastatin downregulated histone deacetylase 1 (HDAC1), resulting in the accumulation of acetylated histone H3 and heat shock protein 70. Furthermore, the expression of phosphoinositide 3-kinase catalytic subunits α and β was reduced under lovastatin treatment, and the phosphorylation of Akt and mammalian target of rapamycin was consequently inhibited. Lovastatin also inhibited the phosphorylation of inhibitor of nuclear factor (NF)-κBα and the translocation of NF-κB into the nucleus. Therefore, the present study demonstrates that lovastatin inhibits the expression of pro-inflammatory mediators, including iNOS and TNF-α, through the suppression of HDAC1 expression, PI3K/Akt phosphorylation and NF-κB translocation in LPS-stimulated RAW264.7 macrophage cells. |
| 2017 | ING2, a tumor associated gene, enhances PAI‑1 and HSPA1A expression with HDAC1 and mSin3A through the PHD domain and C‑terminal. | Mol Med Rep | Inhibitor of growth 2 (ING2) is involved in chromatin remodeling and it has previously been suggested that ING2 may regulate gene expression. The authors previously identified matrix metalloproteinase 13 (MMP13) as a target gene of ING2 in colorectal cancer. The aim of the present study was to identify novel genes regulated by ING2 and histone deacetylase 1 (HDAC1) and to clarify the biological significance of the ING2 structure. The present study generated the point mutant constructs of ING2 and deletion constructs consisting of partial ING2 to investigate the effect on gene expression and verify the interaction with HDAC1, mSin3A and sap30. A microarray was performed to find novel ING2/HDAC1 target genes using cell co‑overexpression of ING2 and HDAC1. Plasminogen activator inhibitor‑1 (PAI‑1) was upregulated with overexpression of ING1b and ING2. The mutation of the PHD domain at 218 significantly attenuated the MMP13 and PAI‑1 expression, whereas the mutation at 224 resulted in increased expression. Furthermore, the expression levels were slightly reduced by the mutation of the C‑terminal. The lack of the PHD domain and the C‑terminal in ING2 resulted in a decreased ability to induce gene expression. The C‑terminal with PHD domain, which lacked the N‑terminal, maintained the transactive function for regulating the target genes. In addition to MMP13 and PAI‑1, eight genes [heat shock protein family A member 1A (HSPA1A), MIR7‑3 host gene, chorionic somatomammotropin hormone 1, growth arrest and DNA damage inducible b, dehydrogenase/reductase 2, galectin 1, myosin light chain 1, and VGF nerve growth factor inducible] were demonstrated to be associated with ING2/HDAC1. The present study demonstrated that ING2/HDAC1 regulated PAI‑1 and HSPA1A expression and the PHD domain and the C‑terminal of ING2, which are binding sites of HDAC1 and mSin3A, are essential regions for the regulation of gene expression. |
| 2017 | Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. | Cell Rep | Macrophages perform critical functions in both innate immunity and cholesterol metabolism. Here, we report that activation of Toll-like receptor 4 (TLR4) in macrophages causes lanosterol, the first sterol intermediate in the cholesterol biosynthetic pathway, to accumulate. This effect is due to type I interferon (IFN)-dependent histone deacetylase 1 (HDAC1) transcriptional repression of lanosterol-14α-demethylase, the gene product of Cyp51A1. Lanosterol accumulation in macrophages, because of either treatment with ketoconazole or induced conditional disruption of Cyp51A1 in mouse macrophages in vitro, decreases IFNβ-mediated signal transducer and activator of transcription (STAT)1-STAT2 activation and IFNβ-stimulated gene expression. These effects translate into increased survival to endotoxemic shock by reducing cytokine secretion. In addition, lanosterol accumulation increases membrane fluidity and ROS production, thus potentiating phagocytosis and the ability to kill bacteria. This improves resistance of mice to Listeria monocytogenes infection by increasing bacterial clearance in the spleen and liver. Overall, our data indicate that lanosterol is an endogenous selective regulator of macrophage immunity. |
| 2016 | Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies. | Cancer Sci | Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non-histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1-ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T-cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan-HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression-free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib. |
| 2016 | Guizhi-Shaoyao-Zhimu decoction attenuates rheumatoid arthritis partially by reversing inflammation-immune system imbalance. | J Transl Med | Guizhi-Shaoyao-Zhimu decoction (GSZD) has been extensively used for rheumatoid arthritis (RA) therapy. Marked therapeutic efficacy of GSZD acting on RA has been demonstrated in several long-term clinical trials without any significant side effects. However, its pharmacological mechanisms remain unclear due to a lack of appropriate scientific methodology.GSZD's mechanisms of action were investigated using an integrative approach that combined drug target prediction, network analysis, and experimental validation.A total of 77 putative targets were identified for 165 assessed chemical components of GSZD. After calculating the topological features of the nodes and edges in the created drug-target network, we identified a candidate GSZD-targeted signal axis that contained interactions between two putative GSZD targets [histone deacetylase 1 (HDAC1) and heat shock protein 90 kDa alpha, class A member 1 (HSP90AA1)] and three known RA-related targets [NFKB2; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta (IKBKB); and tumor necrosis factor-alpha (TNF-α)]. This signal axis could connect different functional modules that are significantly associated with various RA-related signaling pathways, including T/B cell receptor, Toll-like receptor, NF-kappa B and TNF pathways, as well as osteoclast differentiation. Furthermore, the therapeutic effects and putative molecular mechanisms of GSZD's actions on RA were experimentally validated in vitro and in vivo.GSZD may partially attenuate RA by reversing inflammation-immune system imbalance and regulating the HDAC1-HSP90AA1-NFKB2-IKBKB-TNF-α signaling axis. |
| 2015 | Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells. | Virology | The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4(+) T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4(+) T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4(+) T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the "Shock and Kill" strategy for latently HIV-1 infected cells. |
| 2015 | Transcription factor FOXA2-centered transcriptional regulation network in non-small cell lung cancer. | Biochem Biophys Res Commun | Lung cancer is the leading cause of cancer-mediated death. Although various therapeutic approaches are used for lung cancer treatment, these mainly target the tumor suppressor p53 transcription factor, which is involved in apoptosis and cell cycle arrest. However, p53-targeted therapies have limited application in lung cancer, since p53 is found to be mutated in more than half of lung cancers. In this study, we propose tumor suppressor FOXA2 as an alternative target protein for therapies against lung cancer and reveal a possible FOXA2-centered transcriptional regulation network by identifying new target genes and binding partners of FOXA2 by using various screening techniques. The genes encoding Glu/Asp-rich carboxy-terminal domain 2 (CITED2), nuclear receptor subfamily 0, group B, member 2 (NR0B2), cell adhesion molecule 1 (CADM1) and BCL2-associated X protein (BAX) were identified as putative target genes of FOXA2. Additionally, the proteins including highly similar to heat shock protein HSP 90-beta (HSP90A), heat shock 70 kDa protein 1A variant (HSPA1A), histone deacetylase 1 (HDAC1) and HDAC3 were identified as novel interacting partners of FOXA2. Moreover, we showed that FOXA2-dependent promoter activation of BAX and p21 genes is significantly reduced via physical interactions between the identified binding partners and FOXA2. These results provide opportunities to understand the FOXA2-centered transcriptional regulation network and novel therapeutic targets to modulate this network in p53-deficient lung cancer. |
| 2015 | Acetylation of HDAC1 and degradation of SIRT1 form a positive feedback loop to regulate p53 acetylation during heat-shock stress. | Cell Death Dis | The tumor suppressor p53 is an essential transcription factor that sensitively regulates cellular responses to various stresses. Acetylation, a critically important posttranslational modification of p53, is induced in response to cellular stresses. P53 acetylation level strongly correlates with protein stability and activity. The steady-state level of p53 acetylation is balanced by dynamic acetylation and deacetylation. Despite the function of p53 acetylation being well studied, how the steady state of p53 acetylation level is regulated in response to cellular stresses remains unclear. In particular, the dynamic regulation of the deacetylase activities responsible for p53 deacetylation during cellular stress is unknown. In the current study, we investigated the dynamic regulation of HDAC1 (histone deacetylase 1) and SIRT1 (sirtuin 1), two major enzymes for p53 deacetylation, during cell stress. We found that various cell stress events induce HDAC1 acetylation. The increased level of HDAC1 acetylation correlates with the level of p53 acetylation. Acetylated HDAC1 loses the ability to deacetylate p53. Cellular stresses also promote the decline of the SIRT1 protein in a proteasome-dependent pathway, which also results in the increase of p53 acetylation. Importantly, the decreased level of SIRT1 also contributes to the accumulation of HDAC1 acetylation as SIRT1 deacetylates HDAC1. Therefore, the increase of HDAC1 acetylation and reduced level of SIRT1 protein during cellular stress directly link to the induction of p53 acetylation. These results unveil the mechanism underlying the dynamic regulation of p53 acetylation during cell stress. |
| 2015 | Lysine deacetylases regulate the heat shock response including the age-associated impairment of HSF1. | J Mol Biol | Heat shock factor 1 (HSF1) is critical for defending cells from both acute and chronic stresses. In aging cells, the DNA binding activity of HSF1 deteriorates correlating with the onset of pathological events including neurodegeneration and heart disease. We find that DNA binding by HSF1 is controlled by lysine deacetylases with HDAC7, HDAC9, and SIRT1 distinctly increasing the magnitude and length of a heat shock response (HSR). In contrast, HDAC1 inhibits HSF1 in a deacetylase-independent manner. In aging cells, the levels of HDAC1 are elevated and the HSR is impaired, yet reduction of HDAC1 in aged cells restores the HSR. Our results provide a mechanistic basis for the age-associated regulation of the HSR. Besides HSF1, the deacetylases differentially modulate the activities of unrelated DNA binding proteins. Taken together, our data further support the model that lysine deacetylases are selective regulators of DNA binding proteins. |
| 2013 | TAp73 protein stability is controlled by histone deacetylase 1 via regulation of Hsp90 chaperone function. | J Biol Chem | Histone deacetylases (HDACs) play important roles in fundamental cellular processes, and HDAC inhibitors are emerging as promising cancer therapeutics. p73, a member of the p53 family, plays a critical role in tumor suppression and neural development. Interestingly, p73 produces two classes of proteins with opposing functions: the full-length TAp73 and the N-terminally truncated ΔNp73. In the current study, we sought to characterize the potential regulation of p73 by HDACs and found that histone deacetylase 1 (HDAC1) is a key regulator of TAp73 protein stability. Specifically, we showed that HDAC1 inhibition by HDAC inhibitors or by siRNA shortened the half-life of TAp73 protein and subsequently decreased TAp73 expression under normal and DNA damage-induced conditions. Mechanistically, we found that HDAC1 knockdown resulted in hyperacetylation and inactivation of heat shock protein 90, which disrupted the interaction between heat shock protein 90 and TAp73 and thus promoted the proteasomal degradation of TAp73. Functionally, we found that down-regulation of TAp73 was required for the enhanced cell migration mediated by HDAC1 knockdown. Together, we uncover a novel regulation of TAp73 protein stability by HDAC1-heat shock protein 90 chaperone complex, and our data suggest that TAp73 is a critical downstream mediator of HDAC1-regulated cell migration. |
| 2012 | Valproic acid-mediated neuroprotection in retinal ischemia injury via histone deacetylase inhibition and transcriptional activation. | Exp Eye Res | Retinal ischemia plays a central role in several retinal diseases. The pathogenesis of retinal ischemia involves changes in gene expression. Valproic acid (VPA), a broad-spectrum histone deacetylase inhibitor, is an anticonvulsant and mood-stabilizing drug with neuroprotective effects. Here, we investigated whether VPA protects the retina and optic nerve axon from ischemic damage in a rat model and determined a possible protective mechanism. Adult male Wistar rats were randomized into sham, ischemia/reperfusion (I/R)-plus-vehicle, and I/R-plus-VPA groups. Rats received subcutaneous injections of 300 mg/kg VPA or phosphate-buffered saline twice a day after retinal ischemia induced by acute high intraocular pressure. Twenty-four hours after I/R, retinal neuron apoptosis was evaluated using the TUNEL assay. The expression of heat-shock protein 70 (Hsp70), activated-caspase-3, and apoptotic-protease-activating factor-1 (apaf-1), acetylation levels of histone H3, release of cytochrome c, and interaction between Hsp70 and apaf-1 were analyzed by immunoblotting analysis in all groups; the transcriptional activation of the Hsp70 gene and interaction between the Hsp70 promoter with p300 or HDAC1 were analyzed using chromatin immunoprecipitation assay. Seven days after I/R, the histological changes in the retina were evaluated using hematoxylin and eosin staining, and optic nerve axon damage was evaluated using toluidine blue staining and transmission electron microscopy. The density of retinal ganglion cells (RGCs) was analyzed using Fluoro-Gold retrograde labeling at 7, 14, 21 days after I/R. VPA markedly attenuated I/R-induced retinal neuron apoptosis, damage to RGCs, and morphological injury to the retina and optic nerve axons. VPA resulted in the upregulation of Hsp70 and hyperacetylation of histone H3, accompanied by Hsp70 promoter hyperacetylation, which may result from increased p300 recruitment to the Hsp70 promoter. Furthermore, VPA increased the binding between Hsp70 and apaf-1 to block apoptosome formation and reduced the release of cytochrome c and activation of caspase-3 in the retina after I/R. Therefore, VPA-mediated neuroprotection against I/R injury in the retina may involve cytoprotective Hsp70 induction via transcriptional activation and inhibition of the mitochondria-mediated apoptosis pathway. |
| 2011 | Tumor suppressor protein p53 recruits human Sin3B/HDAC1 complex for down-regulation of its target promoters in response to genotoxic stress. | PLoS One | Master regulator protein p53, popularly known as the "guardian of genome" is the hub for regulation of diverse cellular pathways. Depending on the cell type and severity of DNA damage, p53 protein mediates cell cycle arrest or apoptosis, besides activating DNA repair, which is apparently achieved by regulation of its target genes, as well as direct interaction with other proteins. p53 is known to repress target genes via multiple mechanisms one of which is via recruitment of chromatin remodelling Sin3/HDAC1/2 complex. Sin3 proteins (Sin3A and Sin3B) regulate gene expression at the chromatin-level by serving as an anchor onto which the core Sin3/HDAC complex is assembled. The Sin3/HDAC co-repressor complex can be recruited by a large number of DNA-binding transcription factors. Sin3A has been closely linked to p53 while Sin3B is considered to be a close associate of E2Fs. The theme of this study was to establish the role of Sin3B in p53-mediated gene repression. We demonstrate a direct protein-protein interaction between human p53 and Sin3B (hSin3B). Amino acids 1-399 of hSin3B protein are involved in its interaction with N-terminal region (amino acids 1-108) of p53. Genotoxic stress induced by Adriamycin treatment increases the levels of hSin3B that is recruited to the promoters of p53-target genes (HSPA8, MAD1 and CRYZ). More importantly recruitment of hSin3B and repression of the three p53-target promoters upon Adriamycin treatment were observed only in p53(+/+) cell lines. Additionally an increased tri-methylation of the H3K9 residue at the promoters of HSPA8 and CRYZ was also observed following Adriamycin treatment. The present study highlights for the first time the essential role of Sin3B as an important associate of p53 in mediating the cellular responses to stress and in the transcriptional repression of genes encoding for heat shock proteins or proteins involved in regulation of cell cycle and apoptosis. |
| 2009 | Heat-shock factor 1 controls genome-wide acetylation in heat-shocked cells. | Mol Biol Cell | A major regulatory function has been evidenced here for HSF1, the key transcription factor of the heat-shock response, in a large-scale remodeling of the cell epigenome. Indeed, upon heat shock, HSF1, in addition to its well-known transactivating activities, mediates a genome-wide and massive histone deacetylation. Investigating the underlying mechanisms, we show that HSF1 specifically associates with and uses HDAC1 and HDAC2 to trigger this heat-shock-dependent histone deacetylation. This work therefore identifies HSF1 as a master regulator of global chromatin acetylation and reveals a cross-talk between HSF1 and histone deacetylases in the general control of genome organization in response to heat shock. |
| 2009 | Transcriptional induction of GRP78/BiP by histone deacetylase inhibitors and resistance to histone deacetylase inhibitor-induced apoptosis. | Mol Cancer Ther | Histone deacetylase (HDAC) inhibitors are emerging as effective therapies in the treatment of cancer, and the role of HDACs in the regulation of promoters is rapidly expanding. GRP78/BiP is a stress inducible endoplasmic reticulum (ER) chaperone with antiapoptotic properties. We present here the mechanism for repression of the Grp78 promoter by HDAC1. Our studies reveal that HDAC inhibitors specifically induce GRP78, and the induction level is amplified by ER stress. Through mutational analysis, we have identified the minimal Grp78 promoter and specific elements responsible for HDAC-mediated repression. We show the involvement of HDAC1 in the negative regulation of the Grp78 promoter not only by its induction in the presence of the HDAC inhibitors trichostatin A and MS-275 but also by exogenous overexpression and small interfering RNA knockdown of specific HDACs. We present the results of chromatin immunoprecipitation analysis that reveals the binding of HDAC1 to the Grp78 promoter before, but not after, ER stress. Furthermore, overexpression of GRP78 confers resistance to HDAC inhibitor-induced apoptosis in cancer cells, and conversely, suppression of GRP78 sensitizes them to HDAC inhibitors. These results define HDAC inhibitors as new agents that up-regulate GRP78 without concomitantly inducing the ER or heat shock stress response, and suppression of GRP78 in tumors may provide a novel, adjunctive option to enhance anticancer therapies that use these compounds. |
| 2008 | A novel germ cell-specific protein, SHIP1, forms a complex with chromatin remodeling activity during spermatogenesis. | J Biol Chem | To determine the mechanisms of spermatogenesis, it is essential to identify and characterize germ cell-specific genes. Here we describe a protein encoded by a novel germ cell-specific gene, Mm.290718/ZFP541, identified from the mouse spermatocyte UniGene library. The protein contains specific motifs and domains potentially involved in DNA binding and chromatin reorganization. An antibody against Mm.290718/ZFP541 revealed the existence of the protein in testicular spermatogenic cells (159 kDa) but not testicular and mature sperm. Immunostaining analysis of cells at various stages of spermatogenesis consistently showed that the protein is present in spermatocytes and round spermatids only. Transfection assays and immunofluorescence studies indicate that the protein is localized specifically in the nucleus. Proteomic analyses performed to explore the functional characteristics of Mm.290718/ZFP541 showed that the protein forms a unique complex. Other major components of the complex included histone deacetylase 1 (HDAC1) and heat-shock protein A2. Disappearance of Mm.290718/ZFP541 was highly correlated with hyperacetylation in spermatids during spermatogenesis, and specific domains of the protein were involved in the regulation of interactions and nuclear localization of HDAC1. Furthermore, we found that premature hyperacetylation, induced by an HDAC inhibitor, is associated with an alteration in the integrity of Mm.290718/ZFP541 in spermatogenic cells. Our results collectively suggest that the Mm.290718/ZFP541 complex is implicated in chromatin remodeling during spermatogenesis, and we provide further information on the previously unknown molecular mechanism. Consequently, we re-designate Mm.290718/ZFP541 as "SHIP1" representing spermatogenic cell HDAC-interacting protein 1. |
| 2008 | Rapid histone deacetylation and transient HDAC association in the IL-2 promoter region of TSST-1-stimulated T cells. | Immunol Lett | It remains unclear how superantigen induces unresponsiveness in stimulated T cells. We analyzed the chromatin status of the interleukin-2 (IL-2) promoter region in T cells stimulated with toxic shock syndrome toxin-1 (TSST-1) superantigen using T cell receptor-transgenic T cells responding to ovalbumin (OVA) and TSST-1. Compared to OVA stimulation, naïve T cells cultured with TSST-1 showed lower IL-2 expression after transient enhancement. Coincidentally, the acetylated histone H3 (AcH3) level at the IL-2 promoter region was first enhanced, and then decreased, in TSST-1-stimulated T cells. At the reduction stage of AcH3, histone deacetylase-1 (HDAC1) was markedly associated with the IL-2 promoter region in a TSST-1-specific manner without HDAC1 over-expression. The enhancement of HDAC1 association and IL-2 suppression was prevented by pre-treatment with HDAC inhibitor, but not once the anergy status was established. These results suggest that recruitment of HDAC1 in the IL-2 promoter region at the early stimulation stage with TSST-1 plays a pivotal role in sAg-induced anergy. |
| 2008 | Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. | Mol Cancer Res | Histone deacetylases (HDAC) play a critical role in chromatin modification and gene expression. Recent evidence indicates that HDACs can also regulate functions of nonhistone proteins by catalyzing the removal of acetylated lysine residues. Here, we show that the HDAC inhibitor LBH589 down-regulates DNA methyltransferase 1 (DNMT1) protein expression in the nucleus of human breast cancer cells. Cotreatment with the proteasomal inhibitor MG-132 abolishes the ability of LBH589 to reduce DNMT1, suggesting that the proteasomal pathway mediates DNMT1 degradation on HDAC inhibition. Deletion of the NH(2)-terminal 120 amino acids of DNMT1 diminishes LBH589-induced ubiquitination, indicating that this domain is essential for its proteasomal degradation. DNMT1 recruits the molecular chaperone heat shock protein 90 (Hsp90) to form a chaperone complex. Treatment with LBH589 induces hyperacetylation of Hsp90, thereby inhibiting the association of DNMT1 with Hsp90 and promoting ubiquitination of DNMT1. In addition, inactivation of HDAC1 activity by small interfering RNA and MS-275 is associated with Hsp90 acetylation in conjunction with reduction of DNMT1 protein expression. We conclude that the stability of DNMT1 is maintained in part through its association with Hsp90. Disruption of Hsp90 function by HDAC inhibition is a unique mechanism that mediates the ubiquitin-proteasome pathway for DNMT1 degradation. Our studies suggest a new role for HDAC1 and identify a novel mechanism of action for the HDAC inhibitors as down-regulators of DNMT1. |
| 2008 | MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. | Leuk Res | This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene. |
| 2008 | Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1. | Oncogene | Heat shock factor 1 (HSF1), the transcriptional activator of the heat shock genes, is increasingly implicated in cancer. We have shown that HSF1 binds to the corepressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. HSF1-MTA1 complex formation was strongly induced by the transforming ligand heregulin and complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2alpha, all components of the NuRD corepressor complex. These complexes were induced to assemble on the chromatin of MCF7 breast carcinoma cells and associated with the promoters of estrogen-responsive genes. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer. |
| 2007 | Histone deacetylase 1 gene expression and sensitization of multidrug-resistant neuroblastoma cell lines to cytotoxic agents by depsipeptide. | J Natl Cancer Inst | Genes that are overexpressed in multidrug-resistant neuroblastomas relative to drug-sensitive neuroblastomas may provide targets for modulating drug resistance.We used microarrays to compare the gene expression profile of two drug-sensitive neuroblastoma cell lines with that of three multidrug-resistant neuroblastoma cell lines. RNA expression of selected overexpressed genes was quantified in 17 neuroblastoma cell lines by reverse transcription-polymerase chain reaction (RT-PCR). Small-interfering RNAs (siRNAs) were used for silencing gene expression. Cytotoxicity of melphalan, carboplatin, etoposide, and vincristine and cytotoxic synergy (expressed as combination index calculated by CalcuSyn software, where combination index < 1 indicates synergy and > 1 indicates antagonism) were measured in cell lines with a fluorescence-based assay of cell viability. All statistical tests were two-sided.A total of 94 genes were overexpressed in the multidrug-resistant cell lines relative to the drug-sensitive cell lines. Nine genes were selected for RT-PCR analysis, of which four displayed higher mRNA expression in the multidrug-resistant lines than in the drug-sensitive lines: histone deacetylase 1 (HDAC1; 2.3-fold difference, 95% confidence interval [CI] = 1.0-fold to 3.5-fold, P = .025), nuclear transport factor 2-like export factor (4.2-fold difference, 95% CI = 1.7-fold to 7.6-fold, P = .0018), heat shock 27-kDa protein 1 (2.5-fold difference, 95% CI = 1.0-fold to 87.7-fold, P = .028), and TAF12 RNA polymerase II, TATA box-binding protein-associated factor, 20 kDa (2.2-fold, 95% CI = 0.9-fold to 6.0-fold, P = .051). siRNA knockdown of HDAC1 gene expression sensitized CHLA-136 neuroblastoma cells to etoposide up to fivefold relative to the parental cell line or scrambled siRNA-transfected cells (P<.001). Cytotoxicity of the histone deacetylase inhibitor depsipeptide was tested in combination with melphalan, carboplatin, etoposide, or vincristine in five multidrug-resistant neuroblastoma cell lines, and synergistic cytotoxicity was demonstrated at a 90% cell kill of treated cells (combination index < 0.8) in all cell lines.High HDAC1 mRNA expression was associated with multidrug resistance in neuroblastoma cell lines, and inhibition of HDAC1 expression or activity enhanced the cytotoxicity of chemotherapeutic drugs in multidrug-resistant neuroblastoma cell lines. Thus, HDAC1 is a potential therapeutic target in multidrug-resistant neuroblastoma. |
| 2006 | Co-expression of steroid receptors (estrogen receptor alpha and/or progesterone receptors) and Her-2/neu: Clinical implications. | J Steroid Biochem Mol Biol | The response of breast cancer patients to endocrine therapy is guided by the expression of two steroid hormone receptors (HR): estrogen receptor alpha (ERalpha) and/or progesterone receptors (PR). In most laboratories the expression of these predictive markers is studied by immunohistochemistry (IHC) in the breast cancer biopsy samples. Another molecular marker that is being increasingly examined in breast cancer is the oncoprotein Her-2/neu, whose expression/amplification predicts the response to anti-Her-2/neu immunotherapy. The co-expression of HR with that of Her-2/neu is infrequent (most reports agree on this), however, there are some conflicting reports about the clinical implications in term of response to endocrine therapy in the patients that co-express HR and Her-2/neu. We have examined these molecular markers for a number of years in our tumor bank, in this dissertation we will present the method and cut-off to study these markers, the correlations between their expression, and the follow-up of the patients that received tamoxifen-based endocrine therapy, alone or following chemotherapy. We confirmed that the co-expression of HR with Her-2/neu is infrequent, and that these patients presented both a shorter disease free survival and overall survival. Our results will be compared with others related recently published. For example, the aromatase inhibitor anastrozole appears to be an effective endocrine treatment in HR+ patients, irrespective of the Her-2/neu status. We will present data on the molecular mechanisms that could explain the relatively poor outcome of these patients. Heregulin has been found to be a potent inducer of heat shock factor 1 (HSF1) activity and of heat shock protein (Hsp) synthesis in breast cancer cells and HSF1 activation plays a role in the tumorigenic changes induced by heregulin, heregulin exerts its tumorigenic changes through the cell surface tyrosine kinase receptors c-erbB-3 and c-erbB-4 which are able to form dimers with the "ligandless" Her-2/neu. We found that HSF1 associates with metastasis associated protein 1 (MTA1) on the promoters of genes as well as other molecules involved in gene repression (HDAC1, HDAC2) in a manner that is enhanced by either heregulin exposure or heat shock. ERs, although promoting the growth of breast cancer cells are less associated with invasion/metastasis and ER-induced gene expression is involve in this effect. Heregulin can overcome the protective effects of ER and at least a component of this appears to be due to MTA1 repression of ERE dependent transcription, HSF1 and MTA1 cooperate in gene repression. The co-expression of HSF1 and MTA1 was confirmed by IHC in human breast cancer biopsy samples. |
| 2003 | Polyhomeotic stably associates with molecular chaperones Hsc4 and Droj2 in Drosophila Kc1 cells. | Dev Biol | Polycomb group (PcG) proteins silence target loci in Drosophila. Although the mechanism of PcG-mediated silencing remains unknown, there is considerable evidence that PcG proteins act via multiple complexes. We have epitope-tagged Polyhomeotic Proximal, PHP, the major isoform of the proximal product of the polyhomeotic locus, at both termini (F-PHP-HA) and generated a stable Kc1 cell line in order to isolate F-PHP-HA-associated proteins. Using either column chromatography followed by immunoaffinity precipitation or a double immunoaffinity precipitation procedure, we observed multiple proteins that stably associate with F-PHP-HA. Sequencing the five major bands identified PHP-170 and PHP-140 isoforms, Polycomb, Heat shock cognate 4 (Hsc4), and a novel Drosophila J class chaperone we term Droj2. Mutations in both chaperone genes enhance homeotic transformations in PcG genes, suggesting that they have a role in silencing. We show by Western blotting that minor components of F-PHP-HA-associated proteins include TBP, TAF(II)42, TAF(II)85, and p55. However, unlike in PRC1, Psc, TAF(II)62, Modulo, dMI-2, or Rpd3/HDAC1 do not associate with F-PHP-HA. We discuss the role of chaperones and F-PHP-HA-associated proteins in PcG-mediated silencing and the evidence for different complexes containing Polyhomeotic in vivo. |
| 2001 | 5'TG3' interacting factor interacts with Sin3A and represses AR-mediated transcription. | Mol Endocrinol | Like other nuclear receptors, the AR exerts its transcriptional function by binding to cis elements upstream of promoters and interacting with other transcriptional factors (e.g. activators, repressors, and modulators). Among them, histone acetyltransferases (HATs) and histone deacetylases (HDACs) play critical roles in altering the acetylation state of core histones, thereby regulating nuclear hormone receptor-mediated transcription. The nuclear receptor corepressor can repress the TR and RAR in the absence of ligand through either a Sin3A-dependent or -independent manner by recruiting HDACs. AR and some other steroid hormone receptors cannot silence transcription through a similar mechanism in that they are located in the cytoplasm as complexes with heat-shock proteins before exposure to ligand. It has been shown that AR can bind to p160/SRC, cAMP response element-binding protein-binding protein (CBP)/P300 and other coactivators to increase the AR-mediated transcription. However, the molecular mechanism for turning AR from transcriptionally active into silent states is unknown. In this study, we demonstrated that the transcription repressor, 5'TG3' interacting factor (TGIF), selectively represses AR-mediated transcription from several AR-responsive promoters. The repression is mediated through binding of TGIF to the DNA binding domain of AR and is trichostatin sensitive. We also identified a direct protein-protein interaction between TGIF and a transcription corepressor, Sin3A, which suggests a novel pathway for TGIF recruiting HDAC1 to the repression complex. These results provide fresh insight into understanding the mechanism for repressing AR-, and perhaps other steroid hormone receptor-, mediated transcriptions. |