lnflammation-induced epigenetic switches in cancer

Abstract

The link between inflammation and cancer is well established. Chronic inflammation promotes cancer initiation and progression. Various studies showed that the underlying mechanisms involve epigenetic alterations. These epigenetic alterations might culminate into an epigenetic switch that transforms premalignant cells into tumor cells or non-invasive into invasive tumor cells, thereby promoting metastasis. Epigenetic switches require an initiating event, which can be inflammation, whereas the resulting phenotype is inherited without the initiating signal. Epigenetic switches are induced and maintained by DNA methylation, histone modifications, polycomb group (PcG)/trithorax group (TrxG) proteins, and feedback loops consisting of transcription factors and microRNAs. Since epigenetic switches are reversible, they might represent an important basis for the design of novel anticancer therapeutics. This review summarizes published evidence of epigenetic switches in cancer development that are induced by inflammation.

Keywords: Cancer; Cytokine; Epigenetic switch; Epigenetics; Epithelial-mesenchymal transition; Histone modifications; IL-6; Inflammation; Interleukin; Metastasis; Methylation; MicroRNA; NF-κB; Polycomb group proteins; STAT3; TGF-β; Tumor; Tumor microenvironment; miR-200; miR-34; p53.

Fig. 1

Epigenetic switches in cancer initiation. Transient activation of SRC oncogene (a) or co-culture with monocytes (b) triggers the constitutive activation of feedback loops, which induce and maintain transformation of mammary epithelial cells. Modified from Iliopoulos et al. [18] and Rokavec et al. [19]. c Transient exposure to paracrine IL-6 induces constitutive autocrine IL-6 production by cancer cells. d Transient suppression of HNF4A results in permanent activation of an inflammatory feedback loop that induces oncogenic transformation of hepatocytes. Modified from Hatziapostolu et al. [94]. Components indicated in red or green are overexpressed/activated or repressed when feedback loops are active, respectively. Dotted arrows indicate transient stimuli, whereas full arrows represent constitutive activation/repression. See text for details

Fig. 2

Epigenetic switches in EMT. a A double-negative feedback loop that maintains either epithelial or mesenchymal cellular state. Modified from Siemens et al. [136]; b IL-6 activated feedback loop that induces EMT and cancer invasion. Components indicated in green maintain epithelial state, whereas components in red induce EMT and maintain mesenchymal state. Modified from Rokavec et al. [143]. See text for details

Fig. 3

Reorganization of histone modifications at selected promoters during epigenetic switches that occur during non-CSC/CSC and EMT/MET conversions. a The EMT transcription factor SNAIL binds to E-boxes in the CDH1 (E-cadherin) promoter and recruits methyltransferases Suz12, G9a, and SUV39H1, which induce the methylation of repressive marks H3K27 and H3K9, resulting in CDH1 silencing, Furthermore, suppression of miR-200b results in the up-regulation of the miR-200b target Suz12. Enhanced levels of Suz12 lead to silencing of CDH1 and subsequent EMT as well as the formation of CSCs. On the contrary, up-regulation of miR-200b suppresses Suz12 expression and induces the conversion of CSCs to non-CSCs. b The bivalent state of the ZEB1 gene enables the switching between low and high ZEB1 expression. Regulatory regions in the ZEB1 gene contain active H3K4me3 and repressive H3K27me3 marks, which maintain low ZEB1 expression. Upon environmental stimuli, such as TGF-β, the repressive H3K27me3 marks are demethylated and expression of ZEB1 is induced, which leads to EMT and an increase of CSC compartments