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Histone deacetylase inhibition and the regulation of cell growth with particular reference to liver pathobiology.

Joanna F, van Grunsven LA, Mathieu V, Sarah S, Sarah D, Karin V, Tamara V, Vera R - J. Cell. Mol. Med. (2009)

Bottom Line: In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing.In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects.Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium. jfraczek@vub.ac.be

ABSTRACT
The transcriptional activity of genes largely depends on the accessibility of specific chromatin regions to transcriptional regulators. This process is controlled by diverse post-transcriptional modifications of the histone amino termini of which reversible acetylation plays a vital role. Histone acetyltransferases (HATs) are responsible for the addition of acetyl groups and histone deacetylases (HDACs) catalyse the reverse reaction. In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing. The elucidation of unequivocal links between aberrant action of HDACs and tumorigenesis lies at the base of key scientific importance of these enzymes. In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects. Consequently, the dynamic quest for HDAC inhibitors (HDIs) as a new class of anticancer drugs was set off, resulting in a number of compounds that are currently evaluated in clinical trials. Ironically, the knowledge with respect to the expression pattern and function of individual HDAC isoenzymes remains largely elusive. In the present review, we provide an update of the current knowledge on the involvement of HDACs in the regulation of fundamental cellular processes in the liver, being the main site for drug metabolism within the body. Focus lies on the involvement of HDACs in the regulation of growth of normal and transformed hepatocytes and the transdifferentiation process of stellate cells. Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.

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Schematic representation of HSC activation. Liver damage (caused by viral infection, metabolic disease, drugs, toxins, cholestasis) leads to the transdifferentiation of quiescent HSCs into activated myofibroblast-like cells under the influence of different mediators secreted by resident liver cells as well as non-liver resident cells. The most striking phenotypical changes are the loss of lipid droplets, fibrogenesis and the increase in contractile capacity. During resolution of liver damage, it is not yet clear what the fate of the activated stellate cells is: re-differentiation into quiescent HSCs or apoptosis of the activated myofibroblast-like cells. Abbreviations not appearing in the text of the current review are: platelet derived growth factor (PDGF), endothelin 1 (ET-1), reactive oxygen species (ROS) and monocyte chemotactic protein 1 (MCP-1). The figure has been adapted from [127].
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fig04: Schematic representation of HSC activation. Liver damage (caused by viral infection, metabolic disease, drugs, toxins, cholestasis) leads to the transdifferentiation of quiescent HSCs into activated myofibroblast-like cells under the influence of different mediators secreted by resident liver cells as well as non-liver resident cells. The most striking phenotypical changes are the loss of lipid droplets, fibrogenesis and the increase in contractile capacity. During resolution of liver damage, it is not yet clear what the fate of the activated stellate cells is: re-differentiation into quiescent HSCs or apoptosis of the activated myofibroblast-like cells. Abbreviations not appearing in the text of the current review are: platelet derived growth factor (PDGF), endothelin 1 (ET-1), reactive oxygen species (ROS) and monocyte chemotactic protein 1 (MCP-1). The figure has been adapted from [127].

Mentions: Liver fibrosis is a disease arising as a result of dysregulated repair processes in reaction to liver insults [124]. It is believed that HSCs are major perpetrators of the pathological changes. HSCs belong to the non-parenchymal subpopulation in the liver. In normal, healthy liver, these cells occupy the space of Disse, embracing the hepatic sinusoids with their long protrusions. In their quiescent state they are known to store retinoids within the numerous cytoplasmic lipid droplets [125]. Upon liver injury, HSCs undergo a complete metamorphosis during a process commonly referred to as ‘transdifferentiation’. HSCs become ‘activated’ and adopt a distinct myofibroblastic phenotype [126]. The latter is characterized by a higher proliferative capacity, fibrogenic and pro-inflammatory properties and enhanced contractility. The cell morphology is also transformed and is accompanied by a loss of lipid droplets [127]. HSC-derived myofibroblasts constitute a prominent cell type in the pathogenesis of liver cirrhosis. It must be stressed that also other cells, including portal fibroblasts, biliary epithelial cells and bone marrow-derived fibrocytes, may give rise to myofibroblast-like cells [125, 128, 129]. A common feature of the whole myofibroblast population, independent of cell origin, is the expression of the myogenic marker α-smooth muscle actin (α-SMA) (Fig. 4) [86].


Histone deacetylase inhibition and the regulation of cell growth with particular reference to liver pathobiology.

Joanna F, van Grunsven LA, Mathieu V, Sarah S, Sarah D, Karin V, Tamara V, Vera R - J. Cell. Mol. Med. (2009)

Schematic representation of HSC activation. Liver damage (caused by viral infection, metabolic disease, drugs, toxins, cholestasis) leads to the transdifferentiation of quiescent HSCs into activated myofibroblast-like cells under the influence of different mediators secreted by resident liver cells as well as non-liver resident cells. The most striking phenotypical changes are the loss of lipid droplets, fibrogenesis and the increase in contractile capacity. During resolution of liver damage, it is not yet clear what the fate of the activated stellate cells is: re-differentiation into quiescent HSCs or apoptosis of the activated myofibroblast-like cells. Abbreviations not appearing in the text of the current review are: platelet derived growth factor (PDGF), endothelin 1 (ET-1), reactive oxygen species (ROS) and monocyte chemotactic protein 1 (MCP-1). The figure has been adapted from [127].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4516460&req=5

fig04: Schematic representation of HSC activation. Liver damage (caused by viral infection, metabolic disease, drugs, toxins, cholestasis) leads to the transdifferentiation of quiescent HSCs into activated myofibroblast-like cells under the influence of different mediators secreted by resident liver cells as well as non-liver resident cells. The most striking phenotypical changes are the loss of lipid droplets, fibrogenesis and the increase in contractile capacity. During resolution of liver damage, it is not yet clear what the fate of the activated stellate cells is: re-differentiation into quiescent HSCs or apoptosis of the activated myofibroblast-like cells. Abbreviations not appearing in the text of the current review are: platelet derived growth factor (PDGF), endothelin 1 (ET-1), reactive oxygen species (ROS) and monocyte chemotactic protein 1 (MCP-1). The figure has been adapted from [127].
Mentions: Liver fibrosis is a disease arising as a result of dysregulated repair processes in reaction to liver insults [124]. It is believed that HSCs are major perpetrators of the pathological changes. HSCs belong to the non-parenchymal subpopulation in the liver. In normal, healthy liver, these cells occupy the space of Disse, embracing the hepatic sinusoids with their long protrusions. In their quiescent state they are known to store retinoids within the numerous cytoplasmic lipid droplets [125]. Upon liver injury, HSCs undergo a complete metamorphosis during a process commonly referred to as ‘transdifferentiation’. HSCs become ‘activated’ and adopt a distinct myofibroblastic phenotype [126]. The latter is characterized by a higher proliferative capacity, fibrogenic and pro-inflammatory properties and enhanced contractility. The cell morphology is also transformed and is accompanied by a loss of lipid droplets [127]. HSC-derived myofibroblasts constitute a prominent cell type in the pathogenesis of liver cirrhosis. It must be stressed that also other cells, including portal fibroblasts, biliary epithelial cells and bone marrow-derived fibrocytes, may give rise to myofibroblast-like cells [125, 128, 129]. A common feature of the whole myofibroblast population, independent of cell origin, is the expression of the myogenic marker α-smooth muscle actin (α-SMA) (Fig. 4) [86].

Bottom Line: In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing.In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects.Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium. jfraczek@vub.ac.be

ABSTRACT
The transcriptional activity of genes largely depends on the accessibility of specific chromatin regions to transcriptional regulators. This process is controlled by diverse post-transcriptional modifications of the histone amino termini of which reversible acetylation plays a vital role. Histone acetyltransferases (HATs) are responsible for the addition of acetyl groups and histone deacetylases (HDACs) catalyse the reverse reaction. In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing. The elucidation of unequivocal links between aberrant action of HDACs and tumorigenesis lies at the base of key scientific importance of these enzymes. In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects. Consequently, the dynamic quest for HDAC inhibitors (HDIs) as a new class of anticancer drugs was set off, resulting in a number of compounds that are currently evaluated in clinical trials. Ironically, the knowledge with respect to the expression pattern and function of individual HDAC isoenzymes remains largely elusive. In the present review, we provide an update of the current knowledge on the involvement of HDACs in the regulation of fundamental cellular processes in the liver, being the main site for drug metabolism within the body. Focus lies on the involvement of HDACs in the regulation of growth of normal and transformed hepatocytes and the transdifferentiation process of stellate cells. Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.

Show MeSH
Related in: MedlinePlus