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Hypoxia‐induced HIF 1 α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis
Author(s) -
Loftus Stacie K.,
Baxter Laura L.,
Cronin Julia C.,
Fufa Temesgen D.,
Pavan William J.
Publication year - 2017
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12579
Subject(s) - gene knockdown , melanocyte , hypoxia (environmental) , melanoma , biology , cancer research , gene expression , gene , gene expression profiling , genetics , chemistry , organic chemistry , oxygen
Summary Hypoxia and HIF 1 α signaling direct tissue‐specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF 1 α knockdown and hypoxia‐induced gene expression changes, this study identifies a melanocyte‐specific, HIF 1 α ‐dependent/hypoxia‐responsive gene expression signature. Integration of these gene expression changes with HIF 1 α Ch IP ‐Seq analysis identifies 81 HIF 1 α direct target genes in melanocytes. The expression levels for 10 of the HIF 1 α direct targets – GAPDH , PKM , PPAT , DARS , DTWD 1 , SEH 1L , ZNF 292 , RLF , AGTRAP , and GPC 6 – are significantly correlated with reduced time of disease‐free status in melanoma by logistic regression (P ‐ value = 0.0013) and ROC curve analysis ( AUC = 0.826, P‐value < 0.0001). This HIF 1 α ‐regulated profile defines a melanocyte‐specific response under hypoxia, and demonstrates the role of HIF 1 α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.