Hypoxia-induced HIF1α targets in melanocytes reveal a molecular profile associated with poor melanoma prognosis

Pigment Cell Melanoma Res. 2017 May;30(3):339-352. doi: 10.1111/pcmr.12579. Epub 2017 Apr 19.


Hypoxia and HIF1α signaling direct tissue-specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1α knockdown and hypoxia-induced gene expression changes, this study identifies a melanocyte-specific, HIF1α-dependent/hypoxia-responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP-Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for 10 of the HIF1α 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 HIF1α-regulated profile defines a melanocyte-specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.

Keywords: HIF1α; hypoxia; melanocyte; melanoma; metastasis.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Base Sequence
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cluster Analysis
  • Disease-Free Survival
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Melanocytes / metabolism*
  • Melanocytes / pathology*
  • Melanoma / genetics*
  • Melanoma / pathology*
  • Mice
  • Nucleotide Motifs / genetics
  • Prognosis
  • Reproducibility of Results


  • Hypoxia-Inducible Factor 1, alpha Subunit