Diabetes Metab J.  2020 Apr;44(2):234-244. 10.4093/dmj.2019.0243.

Histone Deacetylase 9: Its Role in the Pathogenesis of Diabetes and Other Chronic Diseases

• Hu S
• Cho EH
• Lee JY

• KMID: 2502404
• DOI: http://doi.org/10.4093/dmj.2019.0243

Abstract

As a member of the class IIa histone deacetylases (HDACs), HDAC9 catalyzes the deacetylation of histones and transcription factors, commonly leading to the suppression of gene transcription. The activity of HDAC9 is regulated transcriptionally and posttranslationally. HDAC9 is known to play an essential role in regulating myocyte and adipocyte differentiation and cardiac muscle development. Also, recent studies have suggested that HDAC9 is involved in the pathogenesis of chronic diseases, including cardiovascular diseases, osteoporosis, autoimmune disease, cancer, obesity, insulin resistance, and liver fibrosis. HDAC9 modulates the expression of genes related to the pathogenesis of chronic diseases by altering chromatin structure in their promotor region or reducing the transcriptional activity of their respective transcription factors. This review summarizes the current knowledge of the regulation of HDAC9 expression and activity. Also, the roles of HDAC9 in the pathogenesis of chronic diseases are discussed, along with potential underlying mechanisms.

Keyword

Autoimmune diseases; Cardiovascular diseases; Chronic disease; Epigenomics; Histone deacetylases; Neoplasms; Obesity

Figure

• 

  Fig. 1 Mechanisms for the inhibition of gene transcription by histone deacetylase 9 (HDAC9). HDAC9 inhibits gene transcription by inducing deacetylation of transcription factors (TFs) or in the promoter region of genes. (1) HDAC9 directly binds to C-terminal-binding protein (CtBP) and HDAC3, which are recruited to a TF to assemble a co-repressor complex. Then, the co-repressor complex deacetylates histones in the promoter region of a gene, thereby suppressing gene transcription. (2) HDAC9 binds to a TF for its deacetylation, which inhibits the transcriptional activity. (3) Kinases, such as minibrain-related kinase and calcium calmodulin-dependent protein kinase, phosphorylate the nuclear localization signal region of HDAC9 for subsequent 14-3-3 binding, which leads to the exit of HDAC9 from the nucleus and therefore a loss of its activity.

• 

  Fig. 2 The effects of histone deacetylase 9 (HDAC9) on the development of chronic diseases in bone, adipose tissue, heart, and liver. HDAC9 facilitates osteoblast activity while inhibiting osteoclast differentiation, which may explain the protective effects of HDAC9 against osteoporosis in mice. Adipogenic differentiation of pre-adipocytes may help to alleviate hypoxia and dysfunctions of hypertrophied adipose tissue, which is inhibited by HDAC9. Also, mice with the deletion of Hdac9 are protected from diet-induced adipose tissue dysfunctions and systemic insulin resistance. Hdac9 deficiency also enhances cholesterol efflux from macrophages while inhibiting oxidized low-density lipoprotein-induced human endothelial cell apoptosis, indicating HDAC9 may exacerbate cardiovascular disease (CVD) development. Moreover, HDAC9 may contribute to hepatocellular carcinoma (HCC) development by suppressing miR-376a expression, a microRNA that induces the apoptosis of hepatocellular carcinoma cells. HDAC9 is also critical for hepatic stellate cell (HSC) activation and forkhead box O 1 (FOXO1)-dependent gluconeogenesis in the liver. Therefore, it may also be involved in the development of fibrosis and obesity-induced insulin resistance in the liver.

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