Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.

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Zheng H, Gao L, Feng Y, Yuan L, Zhao H, Cornelius LA

Down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.

Cancer Res. 2009 Jan 15;69(2):449-57. doi: 10.1158/0008-5472.CAN-08-2399.

PubMed ID

19147557 [ View in PubMed

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Abstract

Melanoma is the most serious, highly aggressive form of skin cancer with recent dramatic increases in incidence. Current therapies are relatively ineffective, highlighting the need for a better understanding of the molecular mechanisms contributing to the disease. We have previously shown that activation of Rap1 promotes melanoma cell proliferation and migration through the mitogen-activated protein kinase pathway and integrin activation. In the present study, we show that expression of Rap1GAP, a specific negative regulator of Rap1, is decreased in human melanoma tumors and cell lines. Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. In addition, overexpression of Rap1GAP also inhibits focal adhesion formation and decreases melanoma cell migration. Rap1GAP down-regulation is due to its promoter methylation, a mechanism of gene silencing in tumors. Furthermore, treatment of melanoma cells with the demethylating agent 5-aza-2'-deoxycytidine reinduces Rap1GAP expression, followed by decreased Rap1 activity, ERK phosphorylation, and cell proliferation and survival-changes that are significantly blunted in cells transfected by small interfering RNA-mediated Rap1GAP knockdown. Taken together, our findings indicate that down-regulation of Rap1GAP via promoter hypermethylation promotes melanoma cell proliferation, survival, and migration.