1. CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma
- Author
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Li Huang, Vladislava O. Melnikova, Andrey S. Dobroff, Russell R. Braeuer, Menashe Bar-Eli, Hua Wang, Gabriel J. Villares, and Maya Zigler
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Transcription, Genetic ,lcsh:Medicine ,CD146 Antigen ,Biology ,CREB ,Oncology/Skin Cancers ,Small hairpin RNA ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Neoplasm Metastasis ,Phosphorylation ,Cyclic AMP Response Element-Binding Protein ,Promoter Regions, Genetic ,lcsh:Science ,Transcription factor ,Melanoma ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Multidisciplinary ,lcsh:R ,Cell Biology ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Transcription Factor AP-2 ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cancer research ,biology.protein ,Disease Progression ,lcsh:Q ,Biochemistry/Transcription and Translation ,E2F1 Transcription Factor ,Research Article - 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 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.
- Published
- 2010