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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

The histone code. A core histone showing modifications on two different histone tails (H2B and H3). Different histone modifications can positively or negatively influence the generation of others, mediating a complex crosstalk influencing gene expression. Arrowheads indicate positive effects while flat heads indicate negative effects. Dotted arrows display different enzymes, their function and site of action [adapted from Bannister et al. (43)].
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Figure 2: The histone code. A core histone showing modifications on two different histone tails (H2B and H3). Different histone modifications can positively or negatively influence the generation of others, mediating a complex crosstalk influencing gene expression. Arrowheads indicate positive effects while flat heads indicate negative effects. Dotted arrows display different enzymes, their function and site of action [adapted from Bannister et al. (43)].

Mentions: A first example of histone crosstalk is shown by the relationship between H3S10 phosphorylation and H3K14 acetylation (Figure 2). It has been observed that phosphorylation of this serine residue induces the HAT Gcn5 to acetylate K14 on H3. H3S10 phosphorylation was also demonstrated to inhibit H3K9 modifications (45). Other studies have also demonstrated the requirement of H2BK123 monoubiquitination for H3K4 and H3K79 methylation. Specifically, H2BK123 ubiquitination is dispensable for monomethylation of the other two residues, but it is necessary for their di- and trimethylation (46). In addition, it has been shown that a point mutation in H3K14 results in a specific loss of H3K4 trimethylation, but not mono and dimethylation. As H3K14 is a known acetylation site, thus revealing its requirement for H3K4 trimethylation (47).


Functional Role of G9a Histone Methyltransferase in Cancer.

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

The histone code. A core histone showing modifications on two different histone tails (H2B and H3). Different histone modifications can positively or negatively influence the generation of others, mediating a complex crosstalk influencing gene expression. Arrowheads indicate positive effects while flat heads indicate negative effects. Dotted arrows display different enzymes, their function and site of action [adapted from Bannister et al. (43)].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: The histone code. A core histone showing modifications on two different histone tails (H2B and H3). Different histone modifications can positively or negatively influence the generation of others, mediating a complex crosstalk influencing gene expression. Arrowheads indicate positive effects while flat heads indicate negative effects. Dotted arrows display different enzymes, their function and site of action [adapted from Bannister et al. (43)].
Mentions: A first example of histone crosstalk is shown by the relationship between H3S10 phosphorylation and H3K14 acetylation (Figure 2). It has been observed that phosphorylation of this serine residue induces the HAT Gcn5 to acetylate K14 on H3. H3S10 phosphorylation was also demonstrated to inhibit H3K9 modifications (45). Other studies have also demonstrated the requirement of H2BK123 monoubiquitination for H3K4 and H3K79 methylation. Specifically, H2BK123 ubiquitination is dispensable for monomethylation of the other two residues, but it is necessary for their di- and trimethylation (46). In addition, it has been shown that a point mutation in H3K14 results in a specific loss of H3K4 trimethylation, but not mono and dimethylation. As H3K14 is a known acetylation site, thus revealing its requirement for H3K4 trimethylation (47).

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