Hypoxia-induced HIF1[alpha] targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis

Summary Hypoxia and HIF1[alpha] signaling direct tissue-specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1[alpha] knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1[alpha]-dependent/hypoxia-respons...

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Published in:Pigment cell and melanoma research 2017-05, Vol.30 (3), p.339
Main Authors: Loftus, Stacie K, Baxter, Laura L, Cronin, Julia C, Fufa, Temesgen D, Pavan, William J
Format: Article
Language:English
Subjects:
Chromatin
Gene expression
Gene regulation
Glyceraldehyde-3-phosphate dehydrogenase
Hypoxia
Hypoxia-inducible factor 1
Integration
Melanocytes
Melanoma
Metabolism
Metastases
Regression analysis
Transcription
Vascularization
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Summary:Summary Hypoxia and HIF1[alpha] signaling direct tissue-specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1[alpha] knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1[alpha]-dependent/hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1[alpha] ChIP-Seq analysis identifies 81 HIF1[alpha] direct target genes in melanocytes. The expression levels for 10 of the HIF1[alpha] direct targets - GAPDH,PKM,PPAT,DARS,DTWD1,SEH1L,ZNF292,RLF,AGTRAP, and GPC6 - 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 HIF1[alpha]-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1[alpha] as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.
ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12579