HIF1α and HIF2α independently activate SRC to promote melanoma metastases

J Clin Invest. 2013 May;123(5):2078-93. doi: 10.1172/JCI66715. Epub 2013 Apr 8.


Malignant melanoma is characterized by a propensity for early lymphatic and hematogenous spread. The hypoxia-inducible factor (HIF) family of transcription factors is upregulated in melanoma by key oncogenic drivers. HIFs promote the activation of genes involved in cancer initiation, progression, and metastases. Hypoxia has been shown to enhance the invasiveness and metastatic potential of tumor cells by regulating the genes involved in the breakdown of the ECM as well as genes that control motility and adhesion of tumor cells. Using a Pten-deficient, Braf-mutant genetically engineered mouse model of melanoma, we demonstrated that inactivation of HIF1α or HIF2α abrogates metastasis without affecting primary tumor formation. HIF1α and HIF2α drive melanoma invasion and invadopodia formation through PDGFRα and focal adhesion kinase-mediated (FAK-mediated) activation of SRC and by coordinating ECM degradation via MT1-MMP and MMP2 expression. These results establish the importance of HIFs in melanoma progression and demonstrate that HIF1α and HIF2α activate independent transcriptional programs that promote metastasis by coordinately regulating cell invasion and ECM remodeling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Line, Tumor
  • Extracellular Matrix / metabolism
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Microscopy, Fluorescence
  • Mutation
  • Neoplasm Metastasis
  • Oncogenes
  • PTEN Phosphohydrolase / metabolism
  • Proto-Oncogene Proteins B-raf / metabolism
  • RNA, Small Interfering / metabolism
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology


  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • endothelial PAS domain-containing protein 1
  • Focal Adhesion Protein-Tyrosine Kinases
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • PTEN Phosphohydrolase
  • PTEN protein, human