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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 alterations in cancer. Genetic alterations for G9a in different types of cancer from cBioportal (www.cbioportal.org). Genetic alterations are shown as green (mutations), blue (deletions), red (amplifications), and gray (multiple alterations).
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Figure 5: G9a alterations in cancer. Genetic alterations for G9a in different types of cancer from cBioportal (www.cbioportal.org). Genetic alterations are shown as green (mutations), blue (deletions), red (amplifications), and gray (multiple alterations).

Mentions: It has been observed that G9a is overexpressed in a number of cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, aggressive lung cancer, brain cancer, multiple myeloma, and aggressive ovarian carcinoma (Figure 5) (76–79). Higher G9a expression levels were also noted to be associated with poor prognosis (2, 65, 74, 79). Elevated G9a levels were commonly correlated with higher methylation levels, leading to the suppression of important tumor suppressor genes. In breast cancer, the metastasis suppressor genes desmocollin 3 (DSC3) and MASPIN, for instance, were reported to be frequently silenced by an epigenetic mechanism (80). DSC3 is a glycoprotein, belonging to the cadherin superfamily, required for the desmosome-mediated cell-to-cell junction and adhesion (81). MASPIN is a protease inhibitor, which was shown to reduce the ability to induce tumor growth and metastasis (82). Pharmacologic inhibition of G9a has been demonstrated using the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine, as well as RNA interference (RNAi)-mediated silencing. Inhibition of G9a led to the reactivation of the two tumor suppressors concomitantly, with a reduction of H3K9 di-methylation mark (80) suggesting that the activity of G9a may be linked to DNA methylation. A runt-domain transcription factor, RUNX3 is known to act as a tumor suppressor gene in gastric cancer, and its level of expression was dependent on post-translational modifications, such as acetylation and sumoylation. Transcriptional repression of this factor was instead observed to be mediated by methylation with G9a found to be responsible for its hypoxia-mediated silencing, increasing H3K9 di-methylation and decreasing H3 acetylation at the promoter region of the gene (83). In addition, in ovarian cancer, G9a activity promoted the suppression of different tumor suppressors, including CDH1, DUSP5, SPRY4, and PPP1R15A (79). Moreover, as previously mentioned, G9a methylates the tumor suppressor p53, leading to its inactivation (65). It is thus believed that targeting G9a in cancer will lead to the re-expression of important tumor suppressor genes.


Functional Role of G9a Histone Methyltransferase in Cancer.

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

G9a alterations in cancer. Genetic alterations for G9a in different types of cancer from cBioportal (www.cbioportal.org). Genetic alterations are shown as green (mutations), blue (deletions), red (amplifications), and gray (multiple alterations).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4585248&req=5

Figure 5: G9a alterations in cancer. Genetic alterations for G9a in different types of cancer from cBioportal (www.cbioportal.org). Genetic alterations are shown as green (mutations), blue (deletions), red (amplifications), and gray (multiple alterations).
Mentions: It has been observed that G9a is overexpressed in a number of cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, aggressive lung cancer, brain cancer, multiple myeloma, and aggressive ovarian carcinoma (Figure 5) (76–79). Higher G9a expression levels were also noted to be associated with poor prognosis (2, 65, 74, 79). Elevated G9a levels were commonly correlated with higher methylation levels, leading to the suppression of important tumor suppressor genes. In breast cancer, the metastasis suppressor genes desmocollin 3 (DSC3) and MASPIN, for instance, were reported to be frequently silenced by an epigenetic mechanism (80). DSC3 is a glycoprotein, belonging to the cadherin superfamily, required for the desmosome-mediated cell-to-cell junction and adhesion (81). MASPIN is a protease inhibitor, which was shown to reduce the ability to induce tumor growth and metastasis (82). Pharmacologic inhibition of G9a has been demonstrated using the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine, as well as RNA interference (RNAi)-mediated silencing. Inhibition of G9a led to the reactivation of the two tumor suppressors concomitantly, with a reduction of H3K9 di-methylation mark (80) suggesting that the activity of G9a may be linked to DNA methylation. A runt-domain transcription factor, RUNX3 is known to act as a tumor suppressor gene in gastric cancer, and its level of expression was dependent on post-translational modifications, such as acetylation and sumoylation. Transcriptional repression of this factor was instead observed to be mediated by methylation with G9a found to be responsible for its hypoxia-mediated silencing, increasing H3K9 di-methylation and decreasing H3 acetylation at the promoter region of the gene (83). In addition, in ovarian cancer, G9a activity promoted the suppression of different tumor suppressors, including CDH1, DUSP5, SPRY4, and PPP1R15A (79). Moreover, as previously mentioned, G9a methylates the tumor suppressor p53, leading to its inactivation (65). It is thus believed that targeting G9a in cancer will lead to the re-expression of important tumor suppressor genes.

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