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Review
. 2014 Aug 19:4:45.
doi: 10.1186/2045-3701-4-45. eCollection 2014.

Epigenetic regulation in cancer progression

Affiliations
Review

Epigenetic regulation in cancer progression

Eva Baxter et al. Cell Biosci. .

Abstract

Cancer is a disease arising from both genetic and epigenetic modifications of DNA that contribute to changes in gene expression in the cell. Genetic modifications include loss or amplification of DNA, loss of heterozygosity (LOH) as well as gene mutations. Epigenetic changes in cancer are generally thought to be brought about by alterations in DNA and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. Other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. Excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. It is likely that this is a common contributor to the recurrence and spread of the disease. The emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. Epigenetic alterations at both the DNA and histone level are increasingly being recognised as playing a role in tumourigenesis. Recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. In this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. We also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.

Keywords: Acetylation; Cancer; DNA methylation; Demethylation; Epigenetics; Histone modifications; Hypoxia; Transcription.

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Figures

Figure 1
Figure 1
Double Lock Principle. A gene will be transcribed when it is in the open or “unlocked” state. The promoter region is demethylated, histones acetylated and H3K4me marked. If the gene is silenced, in a closed or “locked” state, DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs) and histone demethyltransferases (HDMs) have modified the promoter region, removing the histone acetylation and modifying methylation accordingly. For the gene to be transcribed, the repression marks will need to be lifted to confer the open, “unlocked” state, by the TETs (removal of methylation on the promoter), histone acetyltransferases (HATs) and the HMTs/HDMs. If the DNA exists in any in-between state, with only partial silencing or activation marks, the gene remains repressed, hence the term “Double Lock”.
Figure 2
Figure 2
Transcriptional control in normoxia and hypoxia. (A) In normoxia, proteasomal degradation of HIFs prevents HIF-α binding to a hypoxia response element (HRE) and transcriptional activation does not occur. (B) The expression of other genes can be regulated by methylation at histones H3K9 and H3K27 by G9a and EZH2 respectively to maintain homeostasis. (C-E) In hypoxia, gene expression is regulated at multiple layers; (C) HIF-α is stabilised in hypoxia and is able to bind to HREs and activate transcription. (D) The transcriptional activity of HIF-α can be modulated by co-regulators; G9a methylates chromatin remodelling complex proteins such as Reptin and Pontin in hypoxia. Methylated Reptin negatively regulates transcriptional activation by HIF-α at a subset of HIF-α target genes by recruiting a transcriptional co-repressor. Conversely, Pontin methylation potentiates HIF-α-mediated transcription at another distinct subset of HIF-α target promoters by enhancing the recruitment of a transcriptional co-activator. (E) The expression of histone methyltransferases such as G9a and EZH2 is elevated in hypoxia which leads to silencing of tumour suppressors through the hypermethylation of histones H3K9 and H3K27.

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