Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors

Liu, Ligong; Dong, Lilong; Bourguet, Erika; Fairlie, David P.

doi:10.2174/0929867328666210629160647

Cited by 12 publications

(13 citation statements)

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“…They have classical arginase folding, structurally and mechanically different from sirtuins (class III), which fold into a Rossmann structure and are NAD‐dependent 56,57 . KDAC leads to histone deacetylation, a hallmark of gene silencing 58–60 . Therefore, abnormal hyperacetylation or deacetylation can cause various diseases 61–63 .…”

Section: Ptms Of Histonesmentioning

confidence: 99%

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Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Liu

Guo

et al. 2023

MedComm

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Histones are DNA‐binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute the “histone code.” The relationship between their combination and biological function can be used as an important epigenetic marker. Methylation and demethylation of the same histone residue, acetylation and deacetylation, phosphorylation and dephosphorylation, and even methylation and acetylation between different histone residues cooperate or antagonize with each other, forming a complex network. Histone‐modifying enzymes, which cause numerous histone codes, have become a hot topic in the research on cancer therapeutic targets. Therefore, a thorough understanding of the role of histone post‐translational modifications (PTMs) in cell life activities is very important for preventing and treating human diseases. In this review, several most thoroughly studied and newly discovered histone PTMs are introduced. Furthermore, we focus on the histone‐modifying enzymes with carcinogenic potential, their abnormal modification sites in various tumors, and multiple essential molecular regulation mechanism. Finally, we summarize the missing areas of the current research and point out the direction of future research. We hope to provide a comprehensive understanding and promote further research in this field.

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Section: Ptms Of Histonesmentioning

confidence: 99%

“… 56 , 57 KDAC leads to histone deacetylation, a hallmark of gene silencing. 58 , 59 , 60 Therefore, abnormal hyperacetylation or deacetylation can cause various diseases. 61 , 62 , 63 Acetylation can weaken the binding of histone to negatively charged DNA.…”

Section: Ptms Of Histonesmentioning

confidence: 99%

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Liu

Guo

et al. 2023

MedComm

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“…Furthermore, type IIa HDAC has both an NLS region at the N-terminus and an NES region at the C-terminus, enabling it to shuttle between the nucleus and cytoplasm. Overall, the catalytic domain of type IIa HDAC is similar to that of Type I HDAC (Liu, Dong, et al, 2021). It consists of an α/β domain with several loops forming the substrate binding channel and catalytic active site, with one zinc ion bound at the active site and two potassium/sodium ion binding sites.…”

Section: Structure Of Iiamentioning

confidence: 99%

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Han,

Feng,

et al. 2023

Chem Biol Drug Des

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Epigenetic regulation of genes through posttranslational regulation of proteins is a well‐explored approach for disease treatment, particularly in cancer chemotherapy. Histone deacetylases have shown significant potential as effective drug targets in therapeutic studies aiming to restore epigenetic normality in oncology. Besides their role in modifying histones, histone deacetylases can also catalyze the deacetylation of various nonhistone proteins and participate in the regulation of multiple biological processes. This paper provides a review of the classification, structure, and functional characteristics of the four classes of human histone deacetylases. The increasing abundance of structural information on HDACs has led to the gradual elucidation of structural differences among subgroups and subtypes. This has provided a reasonable explanation for the selectivity of certain HDAC inhibitors. Currently, the US FDA has approved a total of six HDAC inhibitors for marketing, primarily for the treatment of various hematological tumors and a few solid tumors. These inhibitors all have a common pharmacodynamic moiety consisting of three parts: CAP, ZBG, and Linker. In this paper, the structure–effect relationship of HDAC inhibitors is explored by classifying the six HDAC inhibitors into three main groups: isohydroxamic acids, benzamides, and cyclic peptides, based on the type of inhibitor ZBG. However, there are still many questions that need to be answered in this field. In this paper, the structure‐functional characteristics of HDACs and the structural information of the pharmacophore model and enzyme active region of HDAC is are considered, which can help to understand the inhibition mechanism of the compounds as well as the rational design of HDACs. This paper integrates the structural‐functional characteristics of HDACs as well as the pharmacophore model of HDAC is and the structural information of the enzymatic active region, which not only contributes to the understanding of the inhibition mechanism of the compounds, but also provides a basis for the rational design of HDAC inhibitors.

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“…The general status of HDAC inhibitors [25] and the particular challenges in inhibiting class IIa HDACs [20,167] have been described previously. The specific effects of inhibitors of class IIa HDACs in physiology and disease have been recently reviewed elsewhere [20], so instead, we summarise here some of the most potent inhibitors of HDAC7 reported to date. Crystal structures have been reported for human HDAC7 (PDB codes: 3C0Y, 3C0Z, 3C10 [22]; 3ZNR, 3ZNS [168]) and HDAC4 (PDB codes: 5ZOO, 5ZOP [169]; 4CBT, 4CBY [170]; 6FYZ [171]; 5A2S [172]) and they reveal key differences from class I HDACs.…”

Section: Hdac7 Inhibitorsmentioning

confidence: 99%

Histone deacetylase 7: a signalling hub controlling development, inflammation, metabolism and disease

et al. 2022

Self Cite

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Histone deacetylases (HDACs) catalyse removal of acetyl groups from lysine residues on both histone and non‐histone proteins to control numerous cellular processes. Of the 11 zinc‐dependent classical HDACs, HDAC4, 5, 7 and 9 are class IIa HDAC enzymes that regulate cellular and developmental processes through both enzymatic and non‐enzymatic mechanisms. Over the last two decades, HDAC7 has been associated with key roles in numerous physiological and pathological processes. Molecular, cellular, in vivo and disease association studies have revealed that HDAC7 acts through multiple mechanisms to control biological processes in immune cells, osteoclasts, muscle, the endothelium and epithelium. This HDAC protein regulates gene expression, cell proliferation, cell differentiation and cell survival and consequently controls development, angiogenesis, immune functions, inflammation and metabolism. This review focuses on the cell biology of HDAC7, including the regulation of its cellular localisation and molecular mechanisms of action, as well as its associative and causal links with cancer and inflammatory, metabolic and fibrotic diseases. We also review the development status of small molecule inhibitors targeting HDAC7 and their potential for intervention in different disease contexts.

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Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors

Cited by 12 publications

References 0 publications

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

Histone deacetylase 7: a signalling hub controlling development, inflammation, metabolism and disease

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