Histone deacetylase 6 (HDAC6) is an unique subtype of histone deacetylases with two tandem deacetylase domains and substrate specificity for non-histone proteins. It is involved in many important physiological and pathological processes and has become a promising therapeutic target in recent decades. Different kinds of potent HDAC6-selective inhibitors have been reported around the world. This paper reviews the progress in the study of structure and functions of HDAC6 as well as the development of HDAC6-selective inhibitors.
Histone Deacetylase Inhibitors ; pharmacology ; Histone Deacetylases ; chemistry ; Humans ; Substrate Specificity

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

Oogenesis is the basic reproductive process of female mammals and is essential for fertilization and embryo development. Recent studies have shown that epigenetic modifications play an important role in the regulation of mammalian reproductive processes (such as oogenesis, spermatogenesis, preimplantation embryo development and sex differentiation). Taking histone acetylation as an instance, the dynamic changes of histone acetyltransferases (HATs) and deacetylases (HDACs) are involved in the regulation of gene activation and inactivation when numerous key physiological events occur during reproduction. Thereinto, HDAC1 and HDAC2, which are highly homologous in terms of both structure and function, play a pivotal role in murine oogenesis. HDAC1 and 2 jointly regulate the global transcription and the incidence of apoptosis of growing oocytes and affect its subsequent growth and development, which reflects their compensatory function. In addition, HDAC1 and 2 also play a specific part in oogenesis respectively. It has shown that HDAC2 is more critical than HDAC1 for oocyte development, which regulates de novo DNA methylation and chromosome segregation. Reciprocally, HDAC1 is more critical than HDAC2 for preimplantation development. Deficiency of HDAC1 causes the decreased proliferation of embryonic stem cells and the smaller embryoid bodies with irregular shape. In this review, we summarized the role and the current research progress of HDAC1/2 in murine oogenesis, to provide a reference for further understanding the relationship between epigenetic modifications and reproductive regulation.
Acetylation ; Animals ; Embryonic Development ; Female ; Histone Deacetylase 1/metabolism* ; Histone Deacetylase 2/metabolism* ; Histone Deacetylases/metabolism* ; Male ; Mice ; Oocytes ; Oogenesis

As a crucial part of epigenetic regulation, the histone modification catalyzed by histone modification enzymes can alter the chromatin structure and modulate the gene expression. The role of histone modification in disease pathogenesis, especially in tumorigenesis, has become a research hotspot. The deregulation of histone modification, such as the overexpression and gain-of-function mutations of histone methyltransferase EZH2, the inactive mutations of histone methyltransferase MLL2, histone acetyltransferase CREBBP and EP300 are crucial for the development of hematological neoplasms. Some of Epi-drugs such as HDAC inhibitors, EZH2 inhibitors, are already clinically used, some are still in basic research stage, which are important field of new drug development for hematological neoplasms. In this review, the researches advances of basic medical sciences and clinical applications of aberrant histone modifications in hematological neoplasms are summarized.
Cell Transformation, Neoplastic ; Epigenesis, Genetic ; Hematologic Neoplasms ; Histone Deacetylase Inhibitors ; Histone-Lysine N-Methyltransferase ; Histones ; Humans

Mice ; Animals ; Acetylation ; NF-kappa B/metabolism* ; Histone Deacetylases/metabolism* ; Inflammation ; Histone Deacetylase Inhibitors

Histone acetylation is one of the epigenetic modifications. Histone acetylation, which is catalyzed by histone acetyltransferases and negatively regulated by histone deacetylases, plays an important role in a variety of cellular physiological and pathophysiological processes. Recent studies have shown that histone deacetylases are involved in a variety of pathophysiological responses to acute kidney injury, such as apoptosis, dedifferentiation, proliferation and regeneration. This article reviews the role and underlying mechanism of histone deacetylases in acute kidney injury induced by ischemia reperfusion, nephrotoxicants, sepsis and rhabdomyolysis.
Acetylation ; Acute Kidney Injury ; Histone Acetyltransferases/metabolism* ; Histone Deacetylases/metabolism* ; Humans ; Protein Processing, Post-Translational

BACKGROUND: It has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma. METHODS: We studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis. RESULTS: The degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05). CONCLUSIONS: HAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors.
Acetylation ; B-Lymphocytes ; Blotting, Western ; Histone Acetyltransferases ; Histone Deacetylase Inhibitors ; Histone Deacetylases ; Histones ; Immunohistochemistry ; Lymphoma ; Lymphoma, B-Cell ; Lymphoma, T-Cell, Peripheral ; Prognosis ; Pseudolymphoma

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

Topoisomerases and histone deacetylases (HDACs) are considered as important therapeutic targets for a wide range of cancers, due to their association with the initiation, proliferation and survival of cancer cells. Topoisomerases are involved in the cleavage and religation processes of DNA, while HDACs regulate a dynamic epigenetic modification of the lysine amino acid on various proteins. Extensive studies have been undertaken to discover small molecule inhibitor of each protein and thereby, several drugs have been transpired from this effort and successfully approved for clinical use. However, the inherent heterogeneity and multiple genetic abnormalities of cancers challenge the clinical application of these single targeted drugs. In order to overcome the limitations of a single target approach, a novel approach, simultaneously targeting topoisomerases and HDACs with a single molecule has been recently employed and attracted much attention of medicinal chemists in drug discovery. This review highlights the current studies on the discovery of dual inhibitors against topoisomerases and HDACs, provides their pharmacological aspects and advantages, and discusses the challenges and promise of the dual inhibitors.
DNA ; Drug Discovery ; Epigenomics ; Histone Deacetylases* ; Histones* ; Lysine ; Population Characteristics

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