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

Vladislava O Melnikova1, Andrey S Dobroff, Maya Zigler

  • 1Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|September 1, 2010
PubMed
Abstract

Insights

The cAMP-responsive element binding (CREB) protein drives melanoma progression by suppressing AP-2alpha. Inhibiting CREB restores AP-2alpha, impacting melanoma

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Cutaneous melanoma progression is linked to AP-2alpha loss and increased cAMP-responsive element binding (CREB) protein activity.
  • The molecular mechanisms behind AP-2alpha downregulation in melanoma remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which AP-2alpha is lost during melanoma progression.
  • To investigate the role of CREB in regulating AP-2alpha expression and its impact on melanoma phenotype.

Main Methods:

  • Utilized shRNA to silence CREB expression in metastatic melanoma cell lines.
  • Investigated CREB binding to the AP-2alpha promoter.
  • Assessed the impact of CREB modulation on downstream target genes like p21(Waf1) and MCAM/MUC18.

Main Results:

  • Inhibition of CREB phosphorylation and CREB silencing restored AP-2alpha expression in metastatic melanoma cells.
  • CREB binds to the AP-2alpha promoter and induces E2F-1 overexpression, leading to AP-2alpha loss.
  • CREB silencing upregulated AP-2alpha, increasing p21(Waf1) and decreasing MCAM/MUC18.

Conclusions:

  • CREB is identified as a key regulator of the malignant melanoma phenotype.
  • AP-2alpha loss, mediated by CREB, influences melanoma metastatic potential through downstream genes.
  • Targeting CREB may offer a therapeutic strategy for melanoma.

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