BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

OBJECTIVE: To investigate the effects of histone deacetylase (HDAC) levels on the proliferation and apoptosis of Burkitt lymphoma cells, and the changes in related signaling molecules in the PI3K/AKT/mTOR signaling pathway, so as to explore the pathogenesis of Burkitt lymphoma. METHODS: HDAC levels in Burkitt lymphoma were detected by RT-PCR and Western blot. CA46 and RAJI cells were treated with the HDAC selective inhibitor VPA. CCK8 assay was used to detect the proliferation ability of cells. Western Blot was used to measure the expression of apoptosis-related proteins, PI3K/AKT/mTOR signaling pathway proteins and their phosphorylation levels. RESULTS: The expression levels of classⅠ HDAC in Burkitt lymphoma were higher than those in normal cells, and the HDAC1 inhibitor VPA could inhibit the proliferation of CA46 and RAJI cells. VPA decreased HDAC expression in CA46 and RAJI cells, inhibited the phosphorylation of PI3K/AKT/mTOR pathway molecules AKT and p70S6K, increased the expression of apoptotic proteins Cleaved Caspase-3, Cleaved Caspase-8, Cleaved Caspase-9 and Bax, and decreased the expression of anti-apoptotic proteins Bcl-2 and PARP. CONCLUSION Inhibition of HDAC activity can Attenuate the proliferation of Burkitt lymphoma cells and induce apoptosis by inhibiting the PI3K/AKT/mTOR signaling pathway activity.
Humans ; Burkitt Lymphoma/pathology* ; Apoptosis ; Cell Proliferation ; Signal Transduction ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Cell Line, Tumor ; Histone Deacetylases/metabolism* ; TOR Serine-Threonine Kinases/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Phosphorylation

Sepsis is a life-threatening organ dysfunction caused by the host's dysregulated response to infection, with a complex pathogenesis and high mortality rate. Currently, there are no clear and effective treatment drugs available. Epigenetic modification serves as a major mechanism regulating gene expression under pathological and physiological conditions, and it has been shown to play a critical role in regulating the occurrence and development of sepsis. Histone acetylation modification, as a sophisticated epigenetic modification mechanism, plays a crucial regulatory role in many aspects of life. It can jointly regulate the acetylation status of histones through histone acetyltransferase (HAT) and histone deacetylase (HDAC), thereby changing DNA expression and dynamically regulating sepsis related gene expression at the epigenetic level. Previous studies have shown that histone acetylation can participate in the progression of sepsis by regulating inflammatory mediators, nuclear factor-ΚB (NF-ΚB) signaling pathway, autophagy, efferocytosis, ferroptosis, pyroptosis. These mechanisms are promising targets for novel sepsis treatments. In addition, with the deepening of research, it has been found that various selective/non selective histone deacetylase inhibitors (HDACI) can regulate histone acetylation status by acting on different HDAC targets, which has been shown to alleviate organ damage caused by sepsis and improve prognosis in septic animal models. This article further summarizes the role and potential applications of histone acetylation in sepsis, providing new ideas for the treatment of sepsis.
Sepsis/metabolism* ; Acetylation ; Humans ; Histones/metabolism* ; Histone Acetyltransferases/metabolism* ; Histone Deacetylase Inhibitors ; Epigenesis, Genetic ; Histone Deacetylases/metabolism* ; Signal Transduction ; NF-kappa B/metabolism* ; Animals

The HDAs (a subfamily of histone deacetylases), a class of Zn²⁺-dependent histone deacetylases, are highly homologous to the reduced potassium dependency 3 (RPD3) in yeast. HDAs extensively regulate chromosome stability, gene transcription, and protein activity by catalyzing the removal of acetyl group from histone and non-histone lysine residues. HDA-mediated deacetylation is essential for plant growth, development, and responses to abiotic stress. We review the research progress in HDAs regarding the discovery, structures, classification, deacetylation process, and roles in regulating plant responses to abiotic stress. Furthermore, this paper prospects the future research on HDAs, aiming to provide theoretical support for the research on epigenetic regulation mediated by HDAs.
Histone Deacetylases/classification* ; Zinc/metabolism* ; Stress, Physiological/physiology* ; Plants/genetics*

CUDC-101, an effective and multi-target inhibitor of epidermal growth factor receptor (EGFR), histone deacetylase (HDAC), and human epidermal growth factor receptor 2 (HER2), has been reported to inhibit many kinds of cancers, such as acute promyelocytic leukemia and non-Hodgkin's lymphoma. However, no studies have yet investigated whether CUDC-101 is effective against myeloma. Herein, we proved that CUDC-101 effectively inhibits the proliferation of multiple myeloma (MM) cell lines and induces cell apoptosis in a time- and dose-dependent manner. Moreover, CUDC-101 markedly blocked the signaling pathway of EGFR/phosphoinositide-3-kinase (PI3K) and HDAC, and regulated the cell cycle G2/M arrest. Moreover, we revealed through in vivo experiment that CUDC-101 is a potent anti-myeloma drug. Bortezomib is one of the important drugs in MM treatment, and we investigated whether CUDC-101 has a synergistic or additive effect with bortezomib. The results showed that this drug combination had a synergistic anti-myeloma effect by inducing G2/M phase blockade. Collectively, our findings revealed that CUDC-101 could act on its own or in conjunction with bortezomib, which provides insights into exploring new strategies for MM treatment.
Humans ; Antineoplastic Agents/therapeutic use* ; Apoptosis ; Bortezomib/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; ErbB Receptors/antagonists & inhibitors* ; G2 Phase Cell Cycle Checkpoints ; Histone Deacetylase Inhibitors/pharmacology* ; Histone Deacetylases/metabolism* ; M Cells ; Multiple Myeloma/drug therapy*

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

Human adipose-derived stem cells (hASCs) are a promising cell type for bone tissue regeneration. Circular RNAs (circRNAs) have been shown to play a critical role in regulating various cell differentiation and involve in mesenchymal stem cell osteogenesis. However, how circRNAs regulate hASCs in osteogenesis is still unclear. Herein, we found circ_0003204 was significantly downregulated during osteogenic differentiation of hASCs. Knockdown of circ_0003204 by siRNA or overexpression by lentivirus confirmed circ_0003204 could negatively regulate the osteogenic differentiation of hASCs. We performed dual-luciferase reporting assay and rescue experiments to verify circ_0003204 regulated osteogenic differentiation via sponging miR-370-3p. We predicted and confirmed that miR-370-3p had targets in the 3'-UTR of HDAC4 mRNA. The following rescue experiments indicated that circ_0003204 regulated the osteogenic differentiation of hASCs via miR-370-3p/HDAC4 axis. Subsequent in vivo experiments showed the silencing of circ_0003204 increased the bone formation and promoted the expression of osteogenic-related proteins in a mouse bone defect model, while overexpression of circ_0003204 inhibited bone defect repair. Our findings indicated that circ_0003204 might be a promising target to promote the efficacy of hASCs in repairing bone defects.
Adipose Tissue/metabolism* ; Animals ; Cell Differentiation/genetics* ; Cells, Cultured ; Histone Deacetylases/metabolism* ; Humans ; Mice ; MicroRNAs/metabolism* ; Osteogenesis/genetics* ; RNA, Circular/metabolism* ; Repressor Proteins/metabolism* ; Signal Transduction ; Stem Cells/metabolism*

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

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*