更新于：2024-11-01

HDAC7

更新于：2024-11-01

基本信息

别名

DKFZP586J0917、HD7、HD7a

+ [4]

简介

Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).

关联

项与 HDAC7 相关的药物

TMP269

靶点

HDAC5 x HDAC7 x HDAC9

作用机制

HDAC5 modulators [+2]

在研机构-

原研机构

GSK Plc

在研适应症-

非在研适应症-

最高研发阶段-

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HDAC7 相关的临床结果

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100 项与 HDAC7 相关的转化医学

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0 项与 HDAC7 相关的专利（医药）

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403

项与 HDAC7 相关的文献（医药）

2024-11-06·Biochemical Journal

Histone deacetylase 7 activates 6-phosphogluconate dehydrogenase via an enzyme-independent mechanism that involves the N-terminal protein-protein interaction domain

Article

作者: Curson, James E.B. ; Wang, Yizhuo ; Sweet, Matthew J. ; Fairlie, David P. ; Karunakaran, Denuja ; Reid, Robert C. ; Ramnath, Divya ; Das Gupta, Kaustav

Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold signalling complexes. In macrophages, HDAC7 is a cytoplasmic protein with both pro- and anti-inflammatory functions, with the latter activity involving activation of the pentose phosphate pathway (PPP) enzyme 6-phosphogluconate dehydrogenase (6PGD) and the generation of anti-inflammatory metabolite ribulose-5-phosphate. Here, we used ectopic expression systems and biochemical approaches to investigate the mechanism by which HDAC7 promotes 6PGD enzyme activity. We reveal that HDAC7 enzyme activity is not required for its activation of 6PGD and that the N-terminal protein-protein interaction domain of HDAC7 is sufficient to initiate this response. Mechanistically, the N-terminus of HDAC7 increases the affinity of 6PGD for NADP+, promotes the generation of a shorter form of 6PGD, and enhances the formation of higher order protein complexes, implicating its scaffolding function in engagement of the PPP. This contrasts with the pro-inflammatory function of HDAC7 in macrophages, in which it promotes deacetylation of the glycolytic enzyme pyruvate kinase M2 for inflammatory cytokine production.

2024-11-01·Molecular Neurobiology

Mesenchymal Stem Cell-Derived Extracellular Vesicles Alleviate Brain Damage Following Subarachnoid Hemorrhage via the Interaction of miR-140-5p and HDAC7

Article

作者: Fang, Dazhao ; Wang, Runpei ; Chen, Bo ; Lu, Xinyu ; Qian, Yu ; Li, Zheng ; Sun, Eryi

Subarachnoid hemorrhage (SAH) triggers severe neuroinflammation and cognitive impairment, where microglial M1 polarization exacerbates the injury and M2 polarization mitigates damage. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), carrying microRNA (miR)-140-5p, offer therapeutic promise by targeting the cAMP/PKA/CREB pathway and modulating microglial responses, demonstrating a novel approach for addressing SAH-induced brain injury. This research explored the role of miR-140-5p delivered by MSC-EVs in mitigating brain damage following SAH. Serum from SAH patients and healthy individuals was analyzed for miR-140-5p and cAMP levels. The association between miR-140-5p levels, brain injury severity, and patient survival was examined, along with the target relationship between miR-140-5p and histone deacetylases 7 (HDAC7). MSC-EVs were characterized for their ability to cross the blood-brain barrier and modulate the HDAC7/AKAP12/cAMP/PKA/CREB axis, reducing M1 polarization and inflammation. The therapeutic effect of MSC-EV-miR-140-5p was demonstrated in an SAH mouse model, showing reduced neuronal apoptosis and improved neurological function. This study highlights the potential of MSC-EV-miR-140-5p in mitigating SAH-induced neuroinflammation and brain injury, providing a foundation for developing MSC-EV-based treatments for SAH.

2024-10-01·Journal of Cellular and Molecular Medicine

HDAC7 promotes ovarian cancer malignancy via AKT/mTOR signalling pathway

Article

作者: Sheng, Xiugui ; Liu, Xiongxiu ; Hao, Sheng ; Feng, Qi ; Yan, Zhong ; Li, Yanping ; Zhang, Peng ; Sheng, Kai

AbstractOvarian cancer is of the most lethal malignancy and causes serious threat to women health worldwide. A deep understanding of molecular mechanisms underlying ovarian cancer progression is critical for the development of promising therapeutic strategies. In this study, we aimed to employ immunohistochemistry to determine the protein level of HDAC7 in patient tissues, our data showed HDAC7 levels are upregulated in tumour tissues. In addition, we also performed Kaplan–Meier survival analysis to investigate the association between HDAC7 expression and clinical prognosis, and found that HDAC7 expression was associated with poor prognosis in ovarian cancer patients. Inhibition of HDAC7 cells resulted in lower cell proliferation, invasion and colony formation. Furthermore, we also found that HDAC7 inhibition suppressed PI3K/AKT/mTOR pathway. In contrast, exogenous HDAC7 expression activated the PI3K/AKT/mTOR pathway in HDAC7 knockout cells and rescued the cell proliferation, invasion and colony formation. However, inhibition of p‐AKT induced lower cell proliferation, metastasis and colony formation abilities. In murine model, HDAC7 KO significantly decreased the tumour burden. These data indicate that HDAC7 is involved in regulation of PI3K/AKT/mTOR pathway and targeting of HDAC7 could be potential therapeutic strategy in the treatment of ovarian cancer.

项与 HDAC7 相关的新闻（医药）

2024-07-27

·生物探索

Adv Sci丨浙江大学朱成梁/蒋莉/曹戟揭示其在巨噬细胞中去乙酰酶非依赖性促炎功能

引言 IIa类组蛋白去乙酰化酶（IIa类HDAC）在调节必需的细胞代谢和炎症途径中起着关键作用。然而，由于目前抑制剂的全抑制作用以及缺乏探测其表观遗传调控之外的功能的工具，因此很难剖析每种IIa类HDAC异构体的具体作用。 2024年7月25日，浙江大学朱成梁、蒋莉及曹戟共同通讯在Advanced Science 在线发表题为“PROTAC-Mediated HDAC7 Protein Degradation Unveils Its Deacetylase-Independent Proinflammatory Function in Macrophages”的研究论文，该研究中，开发了一种基于PROTAC的新型化合物B4，它选择性地靶向和降解HDAC7，从而有效减弱脂多糖（LPS）刺激的巨噬细胞和小鼠模型中的一组特定促炎细胞因子。通过使用B4作为分子探针，发现了先前探索的HDAC7作用超越其去乙酰化酶功能的证据，表明其在炎症过程中具有更广泛的意义。机制研究表明，HDAC7通过直接与TNF受体相关因子6和TGFβ活化激酶1（TRAF6-TAK1）复合物相互作用，在Toll样受体4（TLR4）信号通路中发挥关键作用，从而启动下游丝裂原活化蛋白激酶/核因子-κB（MAPK/NF-κB）信号级联的激活以及随后的基因转录。这项研究拓展了对HDAC7在复杂炎症网络中的作用的洞察，并强调了其作为抗炎治疗新靶点的治疗潜力。细胞因子是免疫细胞分泌的必需化学信使，可协调正常的免疫反应。通过与细胞受体相互作用，细胞因子激活下游信号级联，引发免疫反应，保护身体免受炎症或感染。因此，维持促炎和抗炎细胞因子的动态平衡对于免疫稳态至关重要。相反，失调的细胞因子产生会破坏这种平衡，导致免疫紊乱，例如自身免疫性疾病，其特征是免疫系统错误地攻击身体自身的组织。大量研究表明，自身免疫性疾病通常伴有过度的巨噬细胞活化和促炎细胞因子释放。因此，失调的细胞因子网络被认为是导致这些疾病的主要因素。然而，由于复杂的免疫网络涉及多种难以解决的信号通路和蛋白质，因此了解自身免疫性疾病的发病机制仍然具有挑战性。此外，虽然针对细胞因子及其受体提供了一种治疗免疫介导炎症疾病的方法，但抑制这些靶标可能会导致不良的副作用，因为许多细胞因子和受体具有多效性。因此，迫切需要开发针对细胞因子信号网络中关键分子节点的新型治疗策略。一种有希望的方法是针对控制细胞因子基因表达的表观遗传调节剂。表观遗传修饰，如组蛋白乙酰化和去乙酰化，在调节基因转录方面至关重要。通过调节表观遗传酶的活性，可能可以微调细胞因子的产生并恢复免疫平衡。组蛋白去乙酰化酶（HDAC）是一种表观遗传酶，可催化组蛋白和非组蛋白上赖氨酸残基的N-ε-乙酰基修饰水解。通过这种去乙酰化活性，HDAC可以调节对免疫细胞分化、活化和代谢至关重要的基因转录。迄今为止，已鉴定出11种锌依赖性HDAC，并分为四个亚类：I类（HDAC1、2、3、8）、IIa类（HDAC4、5、7、9）、IIb类（HDAC6、10）和IV类（HDAC11）。文献和之前的研究表明，HDAC是炎症和免疫的重要调节剂。IIa类HDAC以其相当弱的脱乙酰酶活性而著称，这归因于其催化域内活性酪氨酸突变为组氨酸。与主要位于细胞核中的I类HDAC不同，IIa类HDAC在细胞核和细胞质之间穿梭，除了染色质修饰外，还参与各种细胞活动。 HDAC7敲低可显著减弱LPS刺激的巨噬细胞中的促炎细胞因子产生（Credit: Advanced Science）具体而言，IIa类HDAC具有较大的非催化区域，可充当表观遗传读取器或伪酶，与多种细胞蛋白相互作用。IIa类HDAC的失调或过表达与许多疾病有关，包括代谢紊乱、炎症和癌症。尽管取得了重大进展，但由于当前抑制剂的全抑制作用以及用于研究其脱乙酰化以外的生物学功能的探针有限，对特定IIa类HDAC亚型的研究仍面临挑战。例如，IIa类HDAC的HDAC7在炎症巨噬细胞中上调，在细胞代谢和炎症中起关键作用。然而，其在调节炎症反应中的去乙酰化酶独立功能仍不清楚。最近，蛋白水解靶向嵌合体（PROTAC）已成为一种利用细胞内源性蛋白酶体降解机制来破坏蛋白质功能的新方法。与传统的酶抑制相比，PROTAC介导的蛋白质降解具有几个吸引人的特性，包括持久的功效、增强的选择性以及针对酶和非酶活性的能力。因此，PROTAC方法在研究这些以前具有挑战性的目标方面显示出了巨大的前景。Fischer及其同事通过使用化学蛋白质组学方法探索HDAC的可降解性，进一步推进了这一领域，为开发针对IIa类HDAC的PROTAC提供了富有洞察力的指导。在这项研究中，发现了HDAC7以前未被探索的、不依赖去乙酰化酶的促炎作用，并报道了第一个体内有效的HDAC7特异性降解剂B4。PROTAC化合物B4可有效诱导HDAC7降解，并显著减少脂多糖（LPS）刺激的巨噬细胞和小鼠模型中多种促炎细胞因子的分泌。使用B4作为分子探针，剖析了HDAC7在维持TNF受体相关因子6和TGFβ激活激酶1（TRAF6-TAK1）复合物和调节细胞因子基因转录中的非酶功能。研究强调了HDAC7在Toll样受体4（TLR4）信号通路中的重要作用，并提出使用异构体选择性降解剂靶向HDAC7作为治疗细胞因子介导的自身炎症疾病的潜在治疗方法。参考文献 https://onlinelibrary.wiley.com/doi/10.1002/advs.202309459 责编|探索君排版|探索君文章来源|“iNature” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

蛋白降解靶向嵌合体

2024-05-30

·精准药物

药物筛选中心（暨南大学）对外提供新药筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶、HDAC、COX、GPCR、报告基因、病毒、细菌等筛选模型，能够开展肿瘤、神经系统疾病、心脑血管病、糖尿病、病毒和细菌感染性疾病等领域相关靶标、细胞、机制的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型1）蛋白水平：激酶：Abl, ABL(M351T), ABL(H396P), ABL(Y253F), ABL1 (E255K), ABL1 (G250E), ABL(Q252H), AKT1, AKT2, AKT3, ALK, ALK5, AuroraA, AuroraB, AXL, BRAF, BRAF(V599E), BTK, DDR1, DDR2, EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M), Flt3, FLT3(D835Y), FGFR1, FGFR2, FGFR3, FGFR4, Her2, Her4, KIT, MET, IGF-1R, FGFR1, JAK1, JAK2, JAK3, MAPK10, MAPK14, mTOR, TrkA, TrkB, TrkC,TYK2, KDR, SRC, PDGFRa, PDGFRA(D842V), PDGFRb, RET, ZAK。蛋白酶：MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, MMP-14, ADAM5, ADAM10, ADAMTS13, TACE/ADAM17, Furin, Cathepsin E, Cathepsin D, BACE-1, DDP4, DDP8, DDP9, HIV protease-1, PMVII，PMVIV。HDACs：HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6。2）肿瘤细胞活性：近500种肿瘤细胞系；基于Ba/F3的耐药模型3）抗病毒/菌药物筛选：EV71和HSV病毒活性筛选模型；金黄色葡萄球菌、大肠杆菌和沙门氏杆菌等4）体内药效：移植瘤模型对外服务1）体外活性筛选（单剂量抑制率；多剂量IC50）；2）体内药效；3）机制研究；4）药代动力学研究；5）化合物工艺优化、大量订制。咨询合作

临床1期

2024-04-22

·Science Daily

Scientists discover the cellular functions of a family of proteins integral to inflammatory diseases

In a scientific breakthrough, researchers have revealed the biological mechanisms by which a family of proteins known as histone deacetylases (HDACs) activate immune system cells linked to inflammatory bowel disease (IBD) and other inflammatory diseases. In a scientific breakthrough, Mount Sinai researchers have revealed the biological mechanisms by which a family of proteins known as histone deacetylases (HDACs) activate immune system cells linked to inflammatory bowel disease (IBD) and other inflammatory diseases. This discovery, reported in Proceedings of the National Academy of Sciences (PNAS), could potentially lead to the development of selective HDAC inhibitors designed to treat types of IBD such as ulcerative colitis and Crohn's disease. "Our understanding of the specific function of class II HDACs in different cell types has been limited, impeding development of therapies targeting this promising drug target family," says senior author Ming-Ming Zhou, PhD, Dr. Harold and Golden Lamport Professor in Physiology and Biophysics and Chair of the Department of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. "Through our proof-of-concept study, we're unraveling the mechanisms of class II HDACs, providing essential knowledge to explore their therapeutic potential for safer and more effective disease treatments." The Mount Sinai team focused specifically on class IIa HDACs, which exhibit more tissue-specific functions than class I HDACs, which act more broadly. Among the 18 histone deacetylases discovered to date in mammals, HDAC4 and HDAC7 -- both class IIa HDACs -- stand out for their roles in regulating the development and differentiation of Th17 cells. These cells are known for producing interleukin-17 (IL-17), a highly inflammatory cytokine associated with a spectrum of disorders, including IBD, multiple sclerosis, and rheumatoid arthritis. Given the strong correlation between excessive Th17 cell activity and human disease, scientists have focused on pharmacological or genetic interventions targeting HDAC4/7 to mitigate Th17 cell-mediated inflammation. In their groundbreaking study, the Mount Sinai researchers delineated a previously unrecognized mechanism by which HDAC4 and HDAC7 operate independently yet cooperatively to govern Th17 cell differentiation and transcription. Transcription is the initial step of gene expression involving copying of the DNA sequence to generate RNA molecules; it is crucial for most biological processes. "The role of class IIa HDACs in Th17 cells and inflammatory disease has been largely unexplored until now," notes lead author Ka Lung Cheung, PhD, Assistant Professor of Pharmacological Sciences at Icahn Mount Sinai. "Mechanistically, we've discovered that class IIa HDACs orchestrate both gene transcriptional activation and repression to steer the process of Th17 cell differentiation. This significant revelation deepens our comprehension of the previously ambiguous role of class IIa HDACs in biology and human disease." As a critical aspect of their investigation, the research team found that a potent class IIa HDAC inhibitor, TMP269, influenced the differentiation of Th17 cells in a mouse model of ulcerative colitis. This pivotal discovery underscores the potential of pharmacological inhibition of class IIa HDACs as a promising therapeutic approach for addressing Th17-related inflammatory and autoimmune diseases, the study reported. Expanding on this foundation of knowledge, researchers in the Zhou Lab and the Cheung Lab at Mount Sinai plan to concentrate on refining class IIa HDAC inhibitors with better efficacies for treating various types of Th17-mediated diseases. "While our study primarily examined inflammatory bowel disease, specifically colitis," says Dr. Zhou, "we believe our findings pave the way for extensive research into advanced therapies targeting severe inflammation in various other pathologies within the human body."