creb inhibits ap-2α expression to regulate the malignant phenotype of melanoma分子抑制ap-2α表达调节黑色素瘤的恶性表型.pdfVIP

CREB Inhibits AP-2a Expression to Regulate the Malignant Phenotype of Melanoma Vladislava O. Melnikova., Andrey S. Dobroff., Maya Zigler, Gabriel J. Villares, Russell R. Braeuer, Hua Wang, Li Huang, Menashe Bar-Eli* Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America Abstract Background: The loss of AP-2a 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-2a 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-2a protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2a. Loss of AP-2a expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2a promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2a expression following CREB silencing increases endogenous p21Waf1 and decreases MCAM/MUC18, both known to be downstream target genes of AP-2a involved in melanoma progression. Conclusions/Significance: Since AP-2a regulates several genes associated with the metastatic potential of melanoma including c- KIT, VEGF, PAR-1, MCAM/MUC18, and p21Waf1, our data identified CREB as a major regulator of the malignant melanoma phenotype. Citation: Melnikova VO, Dobroff AS, Zigler M, Villares GJ, Braeuer RR, et al. (2010) CREB Inhibits AP-2a Expression to Regulate the Malignant Phenotype of Melanoma. PLoS ONE 5(8): e12452. doi:10.1371/journal.pone.0012452