Lysine acetylation is one of the major post-translational modifications and plays critical roles in regulating gene expression and protein function. Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from the lysines of both histone and non-histone proteins. The RPD3 family is the most widely studied HDACs. This article summarizes the regulatory mechanisms of Arabidopsis RPD3 family in several growth and development processes, which provide a reference for studying the mechanisms of RPD3 family members in regulating plant development. Moreover, this review may provide ideas and clues for exploring the functions of other members of HDACs family.
Arabidopsis/metabolism* ; Histone Deacetylases/metabolism* ; Histones ; Plant Development/genetics*

OBJECTIVE: To study the role and mechanism of histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2) in mouse neuronal development. METHODS: The mice with Synapsin1-Cre recombinase were bred with RESULTS: The mice with CONCLUSIONS Deletion of
Animals ; Blotting, Western ; Histone Deacetylase 1/genetics* ; Histone Deacetylase 2 ; Histone Deacetylases/genetics* ; Immunohistochemistry ; Mice ; Neurons/metabolism* ; Signal Transduction

During the past few years, gene expression studies have shown that the perturbation of transcription frequently results in neuronal dysfunction in polyglutamine (PolyQ) diseases such as Huntington's disease (HD). Histone deacetylases (HDACs) act as repressors of transcription through interaction with co-repressor complexes, leading to chromatin remodelling. Aberrant interaction between PolyQ proteins and regulators of transcription could be one mechanism by which transcriptional dysregulation occurs. Here, the authors discuss the possible mechanism of transcriptional dysfunction in PolyQ disease, including the effect of histone acetyltransferases (HATs) and HDACs on pathogenesis, and the potential therapeutic pathways through which histone deacetylase inhibitors (HDACIs) might act to correct the aberrant transcription observed in HD and other PolyQ diseases.
Animals ; Histone Acetyltransferases ; genetics ; metabolism ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; metabolism ; Humans ; Huntington Disease ; drug therapy ; enzymology ; metabolism ; Peptides ; metabolism

Histone modification is an important mechanism in oncogenesis and development of hematologic malignancies. Acetylation of lysine residues on histones and opening chromatin are correlated with activation of genes, whereas lysine residues methylation can result in either activation or repression on expressions of chromatin. The main point of all is deacetylation of histone mediated by histone deacetylases (HDACs). HDAC inhibitors are divided into 4 categories: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides, owning different mechanisms in HDAC inhibition. Many kinds of I/II phase clinical tests showed that all these HDAC inhibitors have obviously therapeutic efficacies in treatment of hematologic malignancies with low poisons. Combination of HDAC inhibitors with DNA demethylation drugs can decrease DNA methylation, increase histone acetylation and recover antioncogene expression. As important parts of epigenetics, histone acetylation and HDAC inhibitors possess positive prospects in treatment of hematologic malignancies. In this review the advances of study on mechanisms of histone modification, HDAC inhibitors and their use in treatment of hematologic malignancies are summarized.
Acetylation ; Hematologic Neoplasms ; drug therapy ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; Histones ; chemistry ; genetics ; metabolism

BACKGROUNDPlacental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process.

METHODSThe human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively.

RESULTSTSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P < 0.001 for 5.0 μmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001).

CONCLUSIONSHDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.

Cell Line ; Histone Deacetylase 1 ; metabolism ; Histone Deacetylase 2 ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Microscopy, Fluorescence ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; RNA, Messenger ; Trophoblasts ; cytology ; metabolism

BACKGROUNDNicotine, a major component of tobacco, is the main cause of smoking addiction. It was found that asthmatic patients who smoke were insensitive to glucocorticoid treatment. In this paper, we investigated whether nicotine could inhibit histone deacetylase 6 activity (HDAC6) and chaperone-dependent activation of the glucocorticoid receptor (GR) in A549 cells. Furthermore, the expression level of heat shock protein 90 (HSP90) was determined.

METHODSQuantitative real-time polymerase chain reaction was used to detect the levels of RNA transcription, and Western blotting was applied to analyze the levels of protein expression of HDAC6, GR, and HSP90 in A549 cells. Moreover, the effects of dexamethasone and trichostatin A were observed in A549 cells.

RESULTSA549 cell proliferation was inhibited in the presence of nicotine, and the level of RNA and protein expression of HDAC6 and GR were down-regulated.

CONCLUSIONSNicotine could inhibit HDAC6 activity and chaperone-dependent activation of GR. This might be the main reason why asthmatic patients who smoke show insensitivity to the glucocorticoid treatment.

Cell Line, Tumor ; Cell Proliferation ; drug effects ; Enzyme Activation ; drug effects ; Histone Deacetylase 6 ; Histone Deacetylases ; genetics ; metabolism ; Humans ; Nicotine ; pharmacology ; Receptors, Glucocorticoid ; genetics ; metabolism

To compare the expression level of metastasis associated-1 (MTA1) gene in high and low metastatic human osteosarcoma cell lines and examine the relationship of MTA1 expression and the metastasis potentiality of osteosarcoma cells, the expression of MTA1 in MG-63 osteosarcoma cell lines with high and low metastasis potential was detected by semiquantitative TR-PCR. Boyden chamber invasion assay was used to evaluate the invasive capacity in vitro in two osteosarcoma cell lines. The low metastasis MG-63 cells were transfected with MTA1 full-length cDNA expression plasmid by lipofectamine and the changes of MTA1 expression and in vitro invasion potential were examined after the transfection. Our results showed that MG63 cell line with high metastasis potential expressed significantly higher MTA1 than that of MG63 cells with low metastasis as reavealed by RT-PCR. The invasion potential of low metastasis MG63 cell line was increased after MTA1 gene transfection. It is concluded that there may be a relationship between MTA 1 and invasive potentiality of human osteosarcoma cells, and the mechanism of MTA1 in osteosarcoma metastasis and its possible role in associated gene therapy deserve further study.
Bone Neoplasms/*metabolism ; Bone Neoplasms/pathology ; Gene Expression Regulation, Neoplastic ; Histone Deacetylases/*biosynthesis ; Histone Deacetylases/genetics ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Osteosarcoma/*metabolism ; Osteosarcoma/pathology ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Repressor Proteins/*biosynthesis ; Repressor Proteins/genetics ; Tumor Cells, Cultured

The mechanisms that regulate angiogenesis in hypoxia or hypoxic microenvironment are modulated by several pro- and antiangiogenic factors. Hypoxia-inducible factors (HIFs) have been established as the basic and major inducers of angiogenesis, but understanding the role of interacting proteins is becoming increasingly important to elucidate the angiogenic processes of a hypoxic response. In particular, with regard to wound healing and the novel therapies for vascular disorders such as ischemic brain and heart attack, it is essential to gain insights in the formation and regulation of HIF transcriptional machineries related to angiogenesis. Further, identification of alternative ways of inhibiting tumor growth by disrupting the growth-triggering mechanisms of increasing vascular supply via angiogenesis depends on the knowledge of how tumor cells develop their own vasculature. Here, we review our findings on the interactions of basic HIFs, HIF-1alpha and HIF-2alpha, with their regulatory binding proteins, histone deacetylase 7 (HDAC7) and translation initiation factor 6 (Int6), respectively. The present results and discussion revealed new regulatory interactions of HIF-related mechanisms.
Animals ; Anoxia/genetics/*metabolism ; Gene Expression Regulation ; Histone Deacetylases/genetics/metabolism ; Humans ; Hypoxia-Inducible Factor 1/genetics/*metabolism ; Neovascularization, Pathologic/genetics/*metabolism

OBJECTIVESTo study the role of histone modification in the regulation of IFN-gamma-activated gene using chromatin immunoprecipitation technique.

METHODSReal-time PCR was used to measure the mRNA level of interferon-gamma-inducible protein 10 (IP-10) in Hela cells. Chromatin immunoprecipitation combined with Real-time PCR was used to check the histone H4 acetylation level at IFN-stimulated response element (ISRE) locus of IP-10 gene.

RESULTSIP-10 was strongly activated by IFN-gamma. The histone H4 deacetylation happened at the ISRE locus when IP-10 was induced by IFN-gamma. The activation of IP-10 and the deacetylation of histone H4 at the ISRE site induced by IFN-gamma were inhibited or blocked by histone deacetylase (HDAC) inhibitor trichostatin A (TSA).

CONCLUSIONThe histone H4 deacetylation at the ISRE site is related with the activation of IP-10 by IFN-gamma.

Acetylation ; Chemokine CXCL10 ; metabolism ; Gene Expression Regulation ; HeLa Cells ; Histone Deacetylases ; genetics ; metabolism ; Histones ; genetics ; metabolism ; Humans ; Interferon-gamma ; genetics ; metabolism ; RNA, Messenger ; genetics

Epigenetic changes frequently occur in human colorectal cancer. Genomic global hypomethylation, gene promoter region hypermethylation, histone modifications, and alteration of miRNA patterns are major epigenetic changes in colorectal cancer. Loss of imprinting(LOI) is associated with colorectal neoplasia. Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation. HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment. Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer. This review is mainly focused on DNA methylation, histone modification, and microRNA changes in colorectal cancer.
Colorectal Neoplasms ; genetics ; metabolism ; CpG Islands ; genetics ; DNA Methylation ; Epigenesis, Genetic ; Folic Acid Deficiency ; genetics ; Genomic Imprinting ; Histone Deacetylase Inhibitors ; metabolism ; Histone Deacetylases ; metabolism ; Histones ; metabolism ; Humans ; MicroRNAs ; genetics ; metabolism ; Promoter Regions, Genetic ; genetics ; RNA, Untranslated ; genetics ; metabolism