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Review
. 2023 Jun;290(11):2805-2832.
doi: 10.1111/febs.16437. Epub 2022 Mar 31.

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

Yizhuo Wang  1   2 , Rishika Abrol  1   2 , Jeffrey Y W Mak  1 , Kaustav Das Gupta  1   2 , Divya Ramnath  1   2 , Denuja Karunakaran  1   2 , David P Fairlie  1   2   3 , Matthew J Sweet  1   2   3
Affiliations
Review

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

Yizhuo Wang et al. FEBS J. 2023 Jun.

Abstract

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.

Keywords: HDAC7; class IIa HDAC; gene regulation; immunometabolism; macrophage.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
Schematic diagram of the human and mouse HDAC7 proteins. Schematic diagrams of the human HDAC7 protein (hHDAC7) (A) and the mouse Hdac7 protein (mHdac7) isoforms that are generated by alternative splicing (B). Hdac7‐spliced (Hdac7‐s) is a full‐length protein generated after excision of a 57 bp intron region. This intron is retained in the Hdac7‐unspliced (Hdac7‐u) isoform, resulting in the presence of premature start codons and use of an alternate downstream translation start site. Consequently, Hdac7‐u lacks the first 22 N‐terminal amino acids (and a binding site for the transcriptional repressor CtBP) that are present in Hdac7‐s. Serine (S) residues that regulate HDAC7 nuclear/cytoplasmic shuttling, as well as a histidine (H) residue that is essential for enzymatic activity, are indicated in yellow and are numbered in the context of the indicated protein (e.g. S178 in mHdac7‐s corresponds to S156 in mHdac7‐u). Proteins used for amino acid numbering are NM_001098416.4 (hHDAC7), NP_062518.2 (mHdac7‐s) and NP_001191207.1 (mHdac7‐u). MEF2, binding site for members of the MEF2 transcription factor family; CtBP, binding site for C‐terminal binding protein; NLS, nuclear localisation signal; NES, nuclear export signal.
Fig. 2
Fig. 2
Subcellular localisation of HDAC7 results in distinct biological functions. (A) Nuclear export of HDAC7 enables inducible gene expression, via its action as a transcriptional derepressor. In response to increased Ca2+ concentrations or upon TCR activation, nuclear HDAC7 is phosphorylated by CaMK1 or PKD1, respectively, resulting in its nuclear export. Cytoplasmic HDAC7 binds to 14‐3‐3 at phosphorylated residues, with the nuclear export of HDAC7 enabling derepression of MEF2‐regulated genes such as NR4A1 (NUR77) in T cells and other cell types. (B) Nuclear import of HDAC7 results in inducible gene expression, via its action as a transcriptional activator. Under hypoxia, HDAC7 shuttles into the nucleus and binds to HIF‐1α and CBP/p300, initiating expression of HIF‐1α target genes such as SLC2A1 (GLUT1) in HEK293 cells. (C) The cytoplasmic HDAC7/14‐3‐3 complex retains β‐catenin in the cytoplasm, preventing its translocation into the nucleus, thus limiting expression of β‐catenin‐dependent genes such as AXIN2. Cytoplasmic functions of HDAC7 have been observed in multiple cell types, for example HUVEC and macrophages. CaMK1, calcium/calmodulin‐dependent kinase 1; ETA, endothelin receptor A; HIF‐1α, hypoxia‐inducible factor 1‐α; MEF2, myocyte enhancer factor‐2; PKD1, protein kinase D1; TCR, T cell receptor.
Fig. 3
Fig. 3
Roles of HDAC7 in physiological and pathophysiological processes. (A) HDAC7 regulates the functions of many cell types in response to a range of differentiation and/or activation signals (see Table 1 for specific transcription factors involved). This class IIa HDAC regulates cell fate choices during both T cell and B cell development, as well as vascular formation and angiogenesis during embryonic development. It also controls the functions and stress responses of cardiomyocytes, as well as metabolic and inflammatory responses in innate immune cells. (B) Because of its diverse physiological roles, dysregulated expression and/or function of HDAC7 has been implicated in numerous pathologies. These include cancer (both solid tumours and leukaemias), as well as inflammatory and metabolic diseases that affect the liver, digestive systems, lung and joints. In contrast, HDAC7 may have a protective role in limiting neurodegenerative disease progression in Huntington's disease (labelled in blue). PSC, primary sclerosing cholangitis.
Fig. 4
Fig. 4
Reassigned structure of MC1568. Correctly assigned regiochemistry for linker (black) that separates capping group (blue) from zinc‐binding hydroxamate group (red).
See this image and copyright information in PMC

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