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

• Published in: PloS one Vol. 5; no. 8; p. e12452
• Main Authors: Melnikova, Vladislava O, Dobroff, Andrey S, Zigler, Maya, Villares, Gabriel J, Braeuer, Russell R, Wang, Hua, Huang, Li, Bar-Eli, Menashe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science (PLoS) 27.08.2010
• Subjects: 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
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0012452

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. 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. 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.