CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma

PLoS One. 2010 Aug 27;5(8):e12452. doi: 10.1371/journal.pone.0012452.


Background: The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.

Methodology/principal findings: Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.

Conclusions/significance: Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype.

Publication types

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

MeSH terms

  • Animals
  • CD146 Antigen / metabolism
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Disease Progression
  • E2F1 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / pathology
  • Neoplasm Metastasis
  • Phosphorylation
  • Promoter Regions, Genetic / genetics
  • Transcription Factor AP-2 / genetics*
  • Transcription Factor AP-2 / metabolism*
  • Transcription, Genetic
  • Up-Regulation


  • CD146 Antigen
  • Cyclic AMP Response Element-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • MCAM protein, human
  • Transcription Factor AP-2