Abstract
Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC.
Highlights
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that are members of the Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (PAS) family
Among the 3 Hap-tag single nucleotide polymorphism (SNP) that were implicated to contribute to the adaptation to high-altitude hypoxia in Sherpas [22], we found binding sites and binding activities for the C/EBP-β, AP-1 or MYC family of transcription factors in a number of cancer cell types in the region of the endothelial PAS domain protein 1 (EPAS1) rs13419896 locus within intron 1 of the gene by surveillance of ChIP-seq datasets from the Encyclopedia of DNA Elements (ENCODE) (S1 Fig)
Enough, when analyzed the sequences using JASPAR Core Vertebrata, we found that relative scores, indices for probability of transcription factor binding, of C/EBP-β and AP-1 were affected by the rs13419896 SNP among the 3 transcription factors as mentioned above; C/EBP-β and AP-1 showed much higher scores of 0.842 and 0.855 in the sequence with A allele at rs13419896, respectively, than those with G allele (0.734 and 0.744)
Summary
Hypoxia-inducible factors (HIFs) are heterodimeric transcription factors that are members of the Per-ARNT-Sim (PAS) family. Expression of human HIF-2α has been identified in lung, carotid bodies, endothelial cells, glial cells, cardiomyocytes, renal fibroblasts and hepatocytes where it plays an important role in the regulation of oxygen physiology [3, 8]. This is of particular importance in the lung as it constitutes the site for oxygen exchange and provides the airliquid interface for this purpose. The effects of these SNPs on expression levels of the EPAS1 are scarcely understood Among these SNPs, we focused on Hap-tag SNPs of the EPAS1 gene that may contribute to the adaptation to high-altitude hypoxia in Sherpas [22], considering lung as a target organ. Bioinformatic analyses prompted us to examine the role of rs13419896 SNP in regulation of the EPAS1 gene expression and an association with prognosis of NSCLC
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