1.Overexpression of Hdac6 extends reproductive lifespan in mice.
Xiaoxi ZHANG ; Jiao YANG ; Haiying WANG ; Renpeng GUO ; Yu YIN ; Dongdong ZHANG ; Qian ZHANG ; Hua WANG ; Zhongcheng ZHOU ; Lingyi CHEN ; Jun ZHOU ; Lin LIU
Protein & Cell 2017;8(5):360-364
2.Down-regulation of HDAC6 Expression Promotes Apoptosis of Human Leukemia K562 Cells.
Ze-Hong LIU ; Bing GUO ; Guan-Hai QIN ; Ying YUAN ; Yu-Dong WANG ; Yi-Ren ZHOU ; Shi-Qing SONG ; Yan-Hua HOU
Journal of Experimental Hematology 2018;26(6):1626-1631
OBJECTIVE:
To study the promoting-apoptosis effect of HDAC6 on the human leukemia cells and its mechanism.
METHODS:
The siRNA interference technology was used to inhibit the expression of HDAC6 gene, the RT-PCR and Western blot were used to detect the expression of HDAC6 and related signal pathway proteins respectively, the flow cytometry and Hoechest staining were used to detect the apoptosis and morphology changes of K562 cells.
RESULTS:
Compared with the periphal blood monocyte and bone marrow stromal cells of healthy volunteers, the expression level of HDAC6 in leukemia cell lines was up-regulated significantly(P<0.05); the flow cytometry and Hoechest staining showed that after interference of HDAC6 gene, the apoptosis of K562 cells increased, moreover the cell morphology was changed; the Western blot detection showed that the interfering HDAC6 increased BAX/BCL-2 ratio and cleaved caspase 3 expression, and activated the MAPK, ATK, ERK signaling pathway.
CONCLUSION
The interferance of HDAC6 can promote the K562 cell apoptosis, its mechanism may relate with activation of MAPK signaling pathway.
Apoptosis
;
Cell Proliferation
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Down-Regulation
;
Histone Deacetylase 6
;
Humans
;
K562 Cells
;
Leukemia
;
RNA, Small Interfering
3.Histone deacetylase 6 promotes skin wound healing by regulating fibroblast migration and differentiation in aged mice.
Yu-Mei QIN ; Ping LI ; Xue-Pan MU ; Zhi-Ming LI ; Chen SUN ; Wen-Long XUE ; Jiao SUN ; Jiao-Jiao BAI ; Yi-Chun ZHU ; Ming-Jie WANG
Acta Physiologica Sinica 2022;74(6):979-992
Skin wound healing tends to slow down with aging, which is detrimental to both minor wound recovery in daily life and the recovery after surgery. The aim of current study was to explore the effect of histone deacetylase 6 (HDAC6) on wound healing during aging. Cultured human dermal fibroblasts (HDFs) and mouse full-thickness skin wound model were used to explore the functional changes of replicative senescent dermal fibroblasts and the effect of aging on skin wound healing. Scratch wound healing assay revealed significantly decreased migration speed of senescent HDFs, and BrdU incorporation assay indicated their considerably retardant proliferation. The protein expression levels of collagen and HDAC6 were significantly decreased in both senescent HDFs and skin tissues from aged mice. HDAC6 activity inhibition with highly selective inhibitor tubastatin A (TsA) or HDAC6 knockdown with siRNA decreased the migration speed of HDFs and considerably suppressed fibroblast differentiation induced by transforming growth factor-β1 (TGF-β1), which suggests the involvement of HDAC6 in regulating fundamental physiological activities of dermal fibroblasts. In vivo full-thickness skin wound healing was significantly delayed in young HDAC6 knockout mice when compared with young wild type mice. In addition, the wound healing was significantly slower in aged wild type mice than that in young wild type mice, and became even worse in aged HDAC6 knockout aged mice. Compared to the aged wild type mice, aged HDAC6 knockout mice exhibited delayed angiogenesis, reduced collagen synthesis, and decreased collagen deposition in skin wounds. Together, these results suggest that delayed skin wound healing in aged mice is associated with impaired fibroblast function. Adequate expression and activity of HDAC6 are required for fibroblasts migration and differentiation.
Humans
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Animals
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Mice
;
Aged
;
Histone Deacetylase 6
;
Skin
;
Wound Healing
;
Cell Movement
;
Collagen/pharmacology*
;
Fibroblasts
;
Mice, Knockout
;
Cells, Cultured
4.Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity.
Yan-Qiong ZHANG ; Chun-Xia SHI ; Dan-Mei ZHANG ; Lu-Yi ZHANG ; Lu-Wen WANG ; Zuo-Jiong GONG
Journal of Integrative Medicine 2023;21(5):464-473
OBJECTIVE:
Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action.
METHODS:
Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe2+, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence.
RESULTS:
Our results show that NRF2 was activated by SFN. LDH, Fe2+, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity.
CONCLUSION
SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.
Humans
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Ferroptosis
;
NF-E2-Related Factor 2/genetics*
;
Liver Failure, Acute/drug therapy*
;
Isothiocyanates/pharmacology*
;
Glutathione
;
Histone Deacetylase 6
5.Trichostatin A Protects Liver against Septic Injury through Inhibiting Toll-Like Receptor Signaling.
So Jin KIM ; Jin Sook PARK ; Do Won LEE ; Sun Mee LEE
Biomolecules & Therapeutics 2016;24(4):387-394
Sepsis, a serious clinical problem, is characterized by a systemic inflammatory response to infection and leads to organ failure. Toll-like receptor (TLR) signaling is intimately implicated in hyper-inflammatory responses and tissue injury during sepsis. Histone deacetylase (HDAC) inhibitors have been reported to exhibit anti-inflammatory properties. The aim of this study was to investigate the hepatoprotective mechanisms of trichostatin A (TSA), a HDAC inhibitor, associated with TLR signaling pathway during sepsis. The anti-inflammatory properties of TSA were assayed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP), a clinically relevant model of sepsis. The mice were intraperitoneally received TSA (1, 2 or 5 mg/kg) 30 min before CLP. The serum and liver samples were collected 6 and 24-h after CLP. TSA inhibited the increased production of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in LPS-stimulated RAW264.7 cells. TSA improved sepsis-induced mortality, attenuated liver injury and decreased serum TNF-α and IL-6 levels. CLP increased the levels of TLR4, TLR2 and myeloid differentiation primary response protein 88 (MyD88) protein expression and association of MyD88 with TLR4 and TLR2, which were attenuated by TSA. CLP increased nuclear translocation of nuclear factor kappa B and decreased cytosolic inhibitor of kappa B (IκB) protein expression, which were attenuated by TSA. Moreover, CLP decreased acetylation of IκB kinase (IKK) and increased association of IKK with IκB and TSA attenuated these alterations. Our findings suggest that TSA attenuates liver injury by inhibiting TLR-mediated inflammatory response during sepsis.
Acetylation
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Animals
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Cytosol
;
Histone Deacetylase Inhibitors
;
Histone Deacetylases
;
Interleukin-6
;
Interleukins
;
Ligation
;
Liver*
;
Mice
;
Mortality
;
NF-kappa B
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Phosphotransferases
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Punctures
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Sepsis
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Toll-Like Receptors*
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Tumor Necrosis Factor-alpha
6.Nicotine inhibits histone deacetylase 6 activity and chaperone-dependent activation of the glucocorticoid receptor in A549 cells.
Li-chao SUN ; Jiang-tao LIN ; Wen LI ; Lan ZHANG ; Tong-liang ZHOU ; Xiao-yan ZHANG
Chinese Medical Journal 2012;125(4):662-666
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
7.Overexpression of Hdac6 enhances resistance to virus infection in embryonic stem cells and in mice.
Dekun WANG ; Qingwen MENG ; Lihong HUO ; Meng YANG ; Lingling WANG ; Xinyu CHEN ; Jianchao WANG ; Zhiguo LI ; Xiaoying YE ; Na LIU ; Qiuyan LI ; Zhen DAI ; Hongsheng OUYANG ; Ning LI ; Jun ZHOU ; Lingyi CHEN ; Lin LIU
Protein & Cell 2015;6(2):152-156
8.Protective effects of histone deacetylase 6 specific inhibitor tubastatin A on subarachnoid hemorrhage in rats and the underlying mechanisms.
Yuwei ZHU ; Haiping ZHENG ; Chunli CHEN
Journal of Central South University(Medical Sciences) 2023;48(2):172-181
OBJECTIVES:
Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.
METHODS:
Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.
RESULTS:
The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .
CONCLUSIONS
HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.
Rats
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Male
;
Animals
;
Rats, Sprague-Dawley
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Subarachnoid Hemorrhage/drug therapy*
;
Vasospasm, Intracranial/metabolism*
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Histone Deacetylase Inhibitors/therapeutic use*
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Neuroprotective Agents/therapeutic use*
;
Histone Deacetylase 6/pharmacology*
;
Apoptosis
;
Brain Injuries/drug therapy*
9.Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner.
Dengwen LI ; Songbo XIE ; Yuan REN ; Lihong HUO ; Jinmin GAO ; Dandan CUI ; Min LIU ; Jun ZHOU
Protein & Cell 2011;2(2):150-160
Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.
Anilides
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pharmacology
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Animals
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Cell Movement
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Cell Polarity
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Cells, Cultured
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Chick Embryo
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Chickens
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Endothelial Cells
;
cytology
;
Histone Deacetylase 6
;
Histone Deacetylases
;
metabolism
;
physiology
;
Humans
;
Hydroxamic Acids
;
pharmacology
;
Mice
;
Microtubule-Associated Proteins
;
metabolism
;
physiology
;
Neovascularization, Physiologic
10.Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells.
Dengwen LI ; Xiaodong SUN ; Linlin ZHANG ; Bing YAN ; Songbo XIE ; Ruming LIU ; Min LIU ; Jun ZHOU
Protein & Cell 2014;5(3):214-223
Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.
Cell Cycle
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Cell Line, Tumor
;
Cell Movement
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Cell Proliferation
;
Gene Knockdown Techniques
;
Histone Deacetylase 6
;
Histone Deacetylases
;
metabolism
;
Humans
;
Microtubule-Associated Proteins
;
metabolism
;
Neoplasm Proteins
;
metabolism
;
Pancreatic Neoplasms
;
enzymology
;
metabolism
;
pathology
;
Protein Binding