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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 structure. G9a structural organization characterized by an automethylation site at its N-terminal end, ankyrin repeats which recognize mono and dimethylated histone H3K9 and by a catalytic SET domain, responsible for the enzymatic activity [adapted from Collins et al. (50)].
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Figure 3: G9a structure. G9a structural organization characterized by an automethylation site at its N-terminal end, ankyrin repeats which recognize mono and dimethylated histone H3K9 and by a catalytic SET domain, responsible for the enzymatic activity [adapted from Collins et al. (50)].

Mentions: G9a is a nuclear histone lysine methyltransferase (HMT) belonging to the Su(var)3-9 family, which mainly catalyzes histone H3 lysine 9 mono- and dimethylation, a reversible modification generally associated with transcriptional gene silencing. Structurally, it is composed of a catalytic SET domain, a domain containing ankyrin repeats (involved in protein–protein interactions) and nuclear localization signals on the N-terminal region (Figure 3) (47–50). G9a SET domain is responsible for the addition of methyl groups on H3, whereas the ankyrin repeats have been observed to represent mono- and dimethyl lysine binding regions. G9a is thus not only able to both methylate histone tails but also able to recognize this modification, functioning as a scaffold for the recruitment of other target molecules on the chromatin (46).


Functional Role of G9a Histone Methyltransferase in Cancer.

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

G9a structure. G9a structural organization characterized by an automethylation site at its N-terminal end, ankyrin repeats which recognize mono and dimethylated histone H3K9 and by a catalytic SET domain, responsible for the enzymatic activity [adapted from Collins et al. (50)].
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: G9a structure. G9a structural organization characterized by an automethylation site at its N-terminal end, ankyrin repeats which recognize mono and dimethylated histone H3K9 and by a catalytic SET domain, responsible for the enzymatic activity [adapted from Collins et al. (50)].
Mentions: G9a is a nuclear histone lysine methyltransferase (HMT) belonging to the Su(var)3-9 family, which mainly catalyzes histone H3 lysine 9 mono- and dimethylation, a reversible modification generally associated with transcriptional gene silencing. Structurally, it is composed of a catalytic SET domain, a domain containing ankyrin repeats (involved in protein–protein interactions) and nuclear localization signals on the N-terminal region (Figure 3) (47–50). G9a SET domain is responsible for the addition of methyl groups on H3, whereas the ankyrin repeats have been observed to represent mono- and dimethyl lysine binding regions. G9a is thus not only able to both methylate histone tails but also able to recognize this modification, functioning as a scaffold for the recruitment of other target molecules on the chromatin (46).

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