The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation

Abstract

A hypoxic microenvironment leads to cancer progression and increases the metastatic potential of cancer cells within tumors via epithelial-mesenchymal transition (EMT) and cancer stemness acquisition. The hypoxic response pathway can occur under oxygen tensions of < 40 mmHg through hypoxia-inducible factors (HIFs), which are considered key mediators in the adaptation to hypoxia. Previous studies have shown that cellular responses to hypoxia are required for EMT and cancer stemness maintenance through HIF-1α and HIF-2α. The principal transcription factors of EMT include Twist, Snail, Slug, Sip1 (Smad interacting protein 1), and ZEB1 (zinc finger E-box-binding homeobox 1). HIFs bind to hypoxia response elements within the promoter region of these genes and also target cancer stem cell-associated genes and mediate transcriptional responses to hypoxia during stem cell differentiation. Acquisition of stemness characteristics in epithelial cells can be induced by activation of the EMT process. The mechanism of these phenotypic changes includes epigenetic alterations, such as DNA methylation, histone modification, chromatin remodeling, and microRNAs. Increased expression of EMT and pluripotent genes also play a role through demethylation of their promoters. In this review, we summarize the role of hypoxia on the acquisition of EMT and cancer stemness and the possible association with epigenetic regulation, as well as their therapeutic applications.

P4HA2 contributes to cervical cancer progression via inducing epithelial-mesenchymal transition

“…A recent study documented that hypoxiainducible factor 1 can enhance P4HA2 expression to subsequently promote collagen fibre alignment [8]. Tumor hypoxia could promote invasion and metastasis by inducing EMT process in various cancers [29][30][31]. We also observed a significant correlation between P4HA2 and HIF1a expression in our study and speculated that hypoxia might regulate the EMT process by enhancing the expression of P4HA2 [32,33].…”

Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression

“…The inactivation of tumor suppressor genes caused by abnormal hypermethylation is particularly important [21]. Studies have shown that hypoxia is one of the important driving forces for DNA methylation imbalance in tumor cells, and interacts with epigenetic regulation mechanisms to promote tumor development [22,23]. In the present study, a total of 12176 DMGs were identified by comparing DNA methylation status in HS-high and HS-low groups.…”

Novel Therapeutic Strategies for Ovarian Cancer Stem Cells

“…TGF-β signaling regulates ovarian CSCs through the modulation of tissue transglutaminase 2 (TGM2), which promotes EMT, metastasis and stem celllike phenotype (164,165). Hypoxia, through the expression of HIF-1α and HIF-2α, regulates CSC-associated genes and induces EMT via the TGF-β signaling pathway, which in turn contributes to stemness (166). Cancer cells with an intermediate EMT phenotype display stem cell-like properties accompanied by enhanced resistance to several anti-cancer drugs [ Figure 5; (124)].…”