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Functional Role of G9a Histone Methyltransferase in Cancer.

Casciello F, Windloch K, Gannon F, Lee JS - Front Immunol (2015)

Bottom Line: Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes.Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies.We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.

View Article: PubMed Central - PubMed

Affiliation: Control of Gene Expression Laboratory, QIMR Berghofer Medical Research Institute , Herston, QLD , Australia ; School of Natural Sciences, Griffith University , Nathan, QLD , Australia.

ABSTRACT
Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes. A number of different epigenetic enzymes are actively involved in the addition or the removal of various covalent modifications, which include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Deregulation of these processes is a hallmark of cancer. For instance, G9a, a histone methyltransferase responsible for histone H3 lysine 9 (H3K9) mono- and dimethylation, has been observed to be upregulated in different types of cancer and its overexpression has been associated with poor prognosis. Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies. Several small molecule inhibitors have been developed to specifically block the epigenetic activity of these enzymes, representing promising therapeutic tools in the treatment of human malignancies, such as cancer. In this review, the role of one of these epigenetic enzymes, G9a, is discussed, focusing on its functional role in regulating gene expression as well as its implications in cancer initiation and progression. We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.

No MeSH data available.


Related in: MedlinePlus

Histone modifications influence chromatin structure and activity. Histone tail modifications lead to a change in histone affinity for the DNA, causing the chromatin to shift between an open (active) and a closed (suppressive) state. An example of a repressive mark is H3K9 methylation, while activation marks correspond to acetylation and H3K4 methylation [adapted from Biran et al. (7)].
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Figure 1: Histone modifications influence chromatin structure and activity. Histone tail modifications lead to a change in histone affinity for the DNA, causing the chromatin to shift between an open (active) and a closed (suppressive) state. An example of a repressive mark is H3K9 methylation, while activation marks correspond to acetylation and H3K4 methylation [adapted from Biran et al. (7)].

Mentions: DNA is packaged into chromatin by histones forming nucleosomes. The nucleosome is organized around an octamer composed of two molecules of each histone protein, H2A, H2B, H3, and H4, with 145 base pairs of DNA wrapped around it (5). Histones are essential proteins characterized by a globular carboxy-terminal domain and a protruding, lysine rich, N-terminal tail. The N-terminal tails of histones are subject to reversible covalent modifications, which ultimately affect gene expression. Histones can be modified by an array of post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation (6). These modifications regulate the ability of transcription factors to access the underlying DNA by modifying histone affinity for its negatively charged sugar backbone, representing a fundamental regulatory mechanism, which is able to impact transcription (Figure 1), replication, and chromatin stability (7, 8).


Functional Role of G9a Histone Methyltransferase in Cancer.

Casciello F, Windloch K, Gannon F, Lee JS - Front Immunol (2015)

Histone modifications influence chromatin structure and activity. Histone tail modifications lead to a change in histone affinity for the DNA, causing the chromatin to shift between an open (active) and a closed (suppressive) state. An example of a repressive mark is H3K9 methylation, while activation marks correspond to acetylation and H3K4 methylation [adapted from Biran et al. (7)].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585248&req=5

Figure 1: Histone modifications influence chromatin structure and activity. Histone tail modifications lead to a change in histone affinity for the DNA, causing the chromatin to shift between an open (active) and a closed (suppressive) state. An example of a repressive mark is H3K9 methylation, while activation marks correspond to acetylation and H3K4 methylation [adapted from Biran et al. (7)].
Mentions: DNA is packaged into chromatin by histones forming nucleosomes. The nucleosome is organized around an octamer composed of two molecules of each histone protein, H2A, H2B, H3, and H4, with 145 base pairs of DNA wrapped around it (5). Histones are essential proteins characterized by a globular carboxy-terminal domain and a protruding, lysine rich, N-terminal tail. The N-terminal tails of histones are subject to reversible covalent modifications, which ultimately affect gene expression. Histones can be modified by an array of post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation (6). These modifications regulate the ability of transcription factors to access the underlying DNA by modifying histone affinity for its negatively charged sugar backbone, representing a fundamental regulatory mechanism, which is able to impact transcription (Figure 1), replication, and chromatin stability (7, 8).

Bottom Line: Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes.Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies.We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.

View Article: PubMed Central - PubMed

Affiliation: Control of Gene Expression Laboratory, QIMR Berghofer Medical Research Institute , Herston, QLD , Australia ; School of Natural Sciences, Griffith University , Nathan, QLD , Australia.

ABSTRACT
Post-translational modifications of DNA and histones are epigenetic mechanisms, which affect the chromatin structure, ultimately leading to gene expression changes. A number of different epigenetic enzymes are actively involved in the addition or the removal of various covalent modifications, which include acetylation, methylation, phosphorylation, ubiquitination, and sumoylation. Deregulation of these processes is a hallmark of cancer. For instance, G9a, a histone methyltransferase responsible for histone H3 lysine 9 (H3K9) mono- and dimethylation, has been observed to be upregulated in different types of cancer and its overexpression has been associated with poor prognosis. Key roles played by these enzymes in various diseases have led to the hypothesis that these molecules represent valuable targets for future therapies. Several small molecule inhibitors have been developed to specifically block the epigenetic activity of these enzymes, representing promising therapeutic tools in the treatment of human malignancies, such as cancer. In this review, the role of one of these epigenetic enzymes, G9a, is discussed, focusing on its functional role in regulating gene expression as well as its implications in cancer initiation and progression. We also discuss important findings from recent studies using epigenetic inhibitors in cell systems in vitro as well as experimental tumor growth and metastasis assays in vivo.

No MeSH data available.


Related in: MedlinePlus