CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.
CREB inhibits AP-2alpha expression to regulate the malignant phenotype of melanoma.
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DOI：
10.1371/journal.pone.0012452
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发表时间：
2010-08-27
期刊：
影响因子：
3.7
通讯作者：
Bar-Eli M
中科院分区：
文献类型：
--
作者：
Melnikova VO;Dobroff AS;Zigler M;Villares GJ;Braeuer RR;Wang H;Huang L;Bar-Eli M
AP-2α缺失和cAMP反应元件结合蛋白活性增强是皮肤黑色素瘤恶性进展的两个标志。然而，导致AP-2α在黑色素瘤进展过程中丢失的分子机制仍不清楚。在这里，我们证明了抑制依赖于蛋白激酶A的CREB的磷酸化，以及通过shRNA沉默CREB的表达，都恢复了两个转移性黑色素瘤细胞系的AP-2α蛋白的表达。此外，在CREB沉默的细胞系中挽救CREB的表达可下调AP-2α的表达。在转移性黑色素瘤中，AP-2α的表达缺失是通过双重机制发生的，包括CREB与AP-2α启动子的结合和CREB诱导的另一癌基因转录因子E2F-1的过表达。沉默后AP-2α表达上调增加内源性p21Waf1，降低MCAM/MUC18，两者都是参与黑色素瘤进展的AP-2α下游靶基因。由于AP-2α调控多个与黑色素瘤转移潜能相关的基因，包括c-Kit、血管内皮生长因子、PAR-1、MCAM/MUC18和p21Waf1，我们的数据证实CREB是恶性黑色素瘤表型的主要调节因子。
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. 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. 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.
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