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

Abstract

Background: The loss of AP-2α 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-2α 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-2α protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2α. Loss of AP-2α expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2α promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2α expression following CREB silencing increases endogenous p21Waf1 and decreases MCAM/MUC18, both known to be downstream target genes of AP-2α involved in melanoma progression. Conclusions/Significance: Since AP-2α regulates several genes associated with the metastatic potential ofmelanoma including c- KIT, VEGF, PAR-1,MCAM/MUC18, and p21Waf1, our data identified CREB as amajor regulator of the malignant melanoma phenotype. © 2010 Melnikova et al.