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.