Mining the Epigenetic Landscape of Tissue Polarity in Search of New Targets for Cancer Therapy

Abstract

The epigenetic nature of cancer encourages the development of inhibitors of epigenetic pathways. Yet, the clinical use for solid tumors of approved epigenetic drugs is meager. We argue that this situation might improve upon understanding the coinfluence between epigenetic pathways and tissue architecture. We present emerging information on the epigenetic control of the polarity axis, a central feature of epithelial architecture created by the orderly distribution of multiprotein complexes at cell-cell and cell-extracellular matrix contacts and altered upon cancer onset (with apical polarity loss), invasive progression (with basolateral polarity loss) and metastatic development (with basoapical polarity imbalance). This information combined with the impact of polarity-related proteins on epigenetic mechanisms of cancer enables us to envision how to guide the choice of drugs specific for distinct epigenetic modifiers, in order to halt cancer development and counter the consequences of polarity alterations.

Epigenetic Alterations in Triple-Negative Breast Cancer—The Critical Role of Extracellular Matrix

“…LSD1 is highly expressed in ERα-negative tumors with mesenchymal signatures and through Snail activation is responsible for silencing genes encoding E-cadherin, claudins and cytokeratins and correlated with poor survival. These results have prompted investigations into the therapeutic utility of LSD1 inhibitors [14].…”

“…EZH2 is also capable of recruiting DNMT1 in many cell types to methylate the promoter regions of various genes including tumor suppressors. It has been suggested that EZH2 enforces the silencing of E-cadherin in basal breast cancers and BRCA1-deficient tumors, and promotes the mesenchymal cell states of these carcinoma cells by driving H3K27me3 that is associated with the CDH1 promoter [14]. Evidence also suggests that the transcription factor Sox4 directly regulates the expression of EZH2 and induces the mesenchymal gene program such as vimentin, fibronectin and N-cadherin genes [17].…”

“…E-cadherin gene (CDH1) is silenced in many types of human cancer, including breast carcinomas, by hypermethylation at CpG islands of the E-cadherin promoter in collaboration with histone deacetylation by HDAC1 and HDAC2 [13]. Many other genes involved in cell polarity (e.g., genes coding for CADM, MYO1A, MPP3, FOXF2) are also silenced by DNA methylation, including breast cancer [14]. Histone methylation is also involved in EMT regulation as it has been shown that the H3K4/K9 demethylase LSD1 can serve as either an activator or a repressor of the EMT-associated gene transcription, in a substrate-specific manner [13].…”

“…It has been shown that certain PRC2 subunits target CDH1, whereas BMI1 through linking to Twist is essential for EMT initiation and the acquisition of the cancer stem cell (CSC) phenotype [13]. B-catenin directly interacts with EZH2 of the polycomb group (PcG), resulting in the enhancement of gene transactivation by the Wnt signaling pathway [14].…”

Epigenetic Regulation of Dlg1, via Kaiso, Alters Mitotic Spindle Polarity and Promotes Intestinal Tumorigenesis

“…Recent work recognizing the importance of the link between polarity and epigenetic pathways in cancer onset and progression (1) has highlighted a need to increase our understanding of these relationships. DNA methylation of CpG dinucleotides is a fundamental epigenetic modification.…”