Epigenetic Regulation of Inflammatory Cytokine-Induced Epithelial-To-Mesenchymal Cell Transition and Cancer Stem Cell Generation

Abstract

The neoplastic transformation of normal to metastatic cancer cells is a complex multistep process involving the progressive accumulation of interacting genetic and epigenetic changes that alter gene function and affect cell physiology and homeostasis. Epigenetic changes including DNA methylation, histone modifications and changes in noncoding RNA expression, and deregulation of epigenetic processes can alter gene expression during the multistep process of carcinogenesis. Cancer progression and metastasis through an 'invasion-metastasis cascade' involving an epithelial-to-mesenchymal cell transition (EMT), the generation of cancer stem cells (CSCs), invasion of adjacent tissues, and dissemination are fueled by inflammation, which is considered a hallmark of cancer. Chronic inflammation is generated by inflammatory cytokines secreted by the tumor and the tumor-associated cells within the tumor microenvironment. Inflammatory cytokine signaling initiates signaling pathways leading to the activation of master transcription factors (TFs) such as Smads, STAT3, and NF-κB. Moreover, the same inflammatory responses also activate EMT-inducing TF (EMT-TF) families such as Snail, Twist, and Zeb, and epigenetic regulators including DNA and histone modifying enzymes and micoRNAs, through complex interconnected positive and negative feedback loops to regulate EMT and CSC generation. Here, we review the molecular regulatory feedback loops and networks involved in inflammatory cytokine-induced EMT and CSC generation.

Keywords: cancer stem cells (CSCs); epigenetic regulators; epithelial-to-mesenchymal cell transition (EMT); feedback regulatory loops; inflammatory cytokine-induced EMT (ICI-EMT); inflammatory cytokines; transcription factors (TFs); tumor microenvironment (TME).

Figure 1

Inflammation is linked to EMT and the generation of cancer stem cells. Inflammatory stimuli initiate signaling transducing pathways leading to the activation of master transcription factors such as Smads, NF-κB, and STAT3. These in turn activate members of oncogenic EMT-TF families such as Snail, Twist, and Zeb, which recruit epigenetic regulators such as DNA and histone tail modifying enzymes, and also affect the expression of noncoding RNAs such as miRNAs. These regulators suppress epithelial cell-specific and activate mesenchymal cell-specific gene expression through interacting positive and negative molecular feedback loops. These inflammatory feedback loops are interconnected generating molecular regulatory circuits and networks to control EMT and CSC generation and maintenance.