HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells

Abstract

Low oxygen levels have shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia inducible factor (HIF), can induce a hESC-like transcriptional program, including the iPSC inducers, OCT4, NANOG, SOX2, KLF4, cMYC and miRNA-302 in eleven cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver and breast tumors). Further, non-degradable forms of HIFα, combined with the traditional iPSC inducers are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4- and HIF1α-positive regions. Further, NANOG and OCT4 expression positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells neurospheres and hESC markers were induced in hypoxia but not in normoxia. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathological conditions.

Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m 6 A-demethylation of NANOG mRNA

“…High NANOG mRNA (23) or protein (41) expression in primary human breast cancers is significantly associated with increased patient mortality. Other groups have implicated HIFs in the direct transcriptional activation of NANOG and other genes encoding pluripotency factors, both in human ESCs (42) and human cancer cells (17). We demonstrated that expression of ALKBH5 was necessary (Figs.…”

“…In hypoxic breast cancer cells, HIFs activate the transcription of target genes that play important roles in tumor growth, angiogenesis, metabolic reprogramming, motility, invasion, metastasis, and resistance to chemotherapy (15,16). Recent studies have demonstrated that HIFs are required for the specification and/or maintenance of BCSCs in response to hypoxia (17)(18)(19)(20)(21) or chemotherapy (22,23), leading to direct or indirect transcriptional regulation of genes encoding the pluripotency factors NANOG, SOX2, and KLF4. In addition, HIF-1α is required for hypoxia-induced epithelial-mesenchymal transition (24), which is also linked to the BCSC phenotype (25).…”

Understanding cancer stem cell heterogeneity and plasticity

“…Recent studies, mostly via in vitro experimental manipulations ( Figure 5D), provide support to these possibilities. For example, culturing cancer cells under low O 2 tension increases the expression of 'stemness' genes and the percentage of phenotypic CSCs [127][128][129]. Experimental EMT and inflammatory cytokines IL-6, IL-8, TGFβ, and TNFα can all promote the manifestation of CSC phenotypes and properties [130][131][132][133][134][135].…”

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

“…Another study observed a somatic rare mutation at the same locus in 1/15 androgen-independent prostate tumours, whereas functional studies demonstrated in androgen-independent prostate cancer cells that the T-allele is associated with increased transcriptional activity and protein expression [28]. Therefore, we hypothesise that carrying the T-allele, which stabilises HIF1a protein and upregulates the HIF1A1 gene expression, may offer a selective advantage to androgen-independent tumour cells through the upregulation of several genes involved in metastasis, angiogenesis, epithelial-to-mesenchymal transition or in other cancer-associated mechanisms [10,23,[31][32][33]. The SNP in HIF1A at locus +1772 represents a germline variant, suggesting a cumulative impact of higher HIF1a expression since birth.…”