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2017 ; 32
(4
): 589-599
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The role of hypoxia on the acquisition of epithelial-mesenchymal transition and
cancer stemness: a possible link to epigenetic regulation
#MMPMID28704917
Yeo CD
; Kang N
; Choi SY
; Kim BN
; Park CK
; Kim JW
; Kim YK
; Kim SJ
Korean J Intern Med
2017[Jul]; 32
(4
): 589-599
PMID28704917
show ga
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-1? and HIF-2?. 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.