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


RESULTS
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
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.
Melnikova
Vladislava O
VO
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Dobroff
Andrey S
AS
Zigler
Maya
M
Villares
Gabriel J
GJ
Braeuer
Russell R
RR
Wang
Hua
H
Huang
Li
L
Bar-Eli
Menashe
M
D000818:Animals; D051929:CD146 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D051929:CD146 Antigen; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497902:MCAM protein, human; D050656:Transcription Factor AP-2
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