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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

G9a in hypoxia. G9a activity is enhanced under hypoxic conditions, leading to the repression of a specific subset of hypoxia-responsive genes. Under similar conditions, G9a can also methylate non-histone proteins, such as Pontin and Reptin, respectively activating or inhibiting the expression of various target genes.
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Figure 4: G9a in hypoxia. G9a activity is enhanced under hypoxic conditions, leading to the repression of a specific subset of hypoxia-responsive genes. Under similar conditions, G9a can also methylate non-histone proteins, such as Pontin and Reptin, respectively activating or inhibiting the expression of various target genes.

Mentions: In mammalian cell lines, G9a activity has been observed to increase under hypoxic conditions through protein accumulation. This increase was correlated with a concomitant increase in the global levels of histone H3K9 di-methylation, which in turn resulted in gene silencing, providing evidence for a critical function of G9a in the repression of genes in response to hypoxia (Figure 4) (61, 62). The ability of G9a to actively repress genes in hypoxic conditions suggests a key role in the promotion of cell survival under this condition. In solid tumors, where hypoxia is a common micro-environmental state, G9a might be functioning as a factor that enhances survival, proliferation, and metastasis of malignant cells.


Functional Role of G9a Histone Methyltransferase in Cancer.

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

G9a in hypoxia. G9a activity is enhanced under hypoxic conditions, leading to the repression of a specific subset of hypoxia-responsive genes. Under similar conditions, G9a can also methylate non-histone proteins, such as Pontin and Reptin, respectively activating or inhibiting the expression of various target genes.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: G9a in hypoxia. G9a activity is enhanced under hypoxic conditions, leading to the repression of a specific subset of hypoxia-responsive genes. Under similar conditions, G9a can also methylate non-histone proteins, such as Pontin and Reptin, respectively activating or inhibiting the expression of various target genes.
Mentions: In mammalian cell lines, G9a activity has been observed to increase under hypoxic conditions through protein accumulation. This increase was correlated with a concomitant increase in the global levels of histone H3K9 di-methylation, which in turn resulted in gene silencing, providing evidence for a critical function of G9a in the repression of genes in response to hypoxia (Figure 4) (61, 62). The ability of G9a to actively repress genes in hypoxic conditions suggests a key role in the promotion of cell survival under this condition. In solid tumors, where hypoxia is a common micro-environmental state, G9a might be functioning as a factor that enhances survival, proliferation, and metastasis of malignant cells.

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