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Spleen Tyrosine Kinase Functions as a Tumor Suppressor in Melanoma Cells by Inducing Senescence-like Growth Arrest

¹ Institut National de la Santé et de la Recherche Médicale U895, Team 1, Biology and Pathologies of Melanocytes; ² Institut National de la Santé et de la Recherche Médicale U576; ³ University of Nice Sophia-Antipolis; and ⁴ Department of Dermatology and ⁵ Department of Clinical Hematology, CHU Nice, Nice, France

Requests for reprints: Sophie Tartare-Deckert, Institut National de la Sante et de la Recherche Medicale U895, Faculté de Médecine, 28 Avenue de Valombrose, 06107 Nice Cédex 2, France. Phone: 33-493-377790; Fax: 33-493-811404; E-mail: tartare{at}unice.fr.

Key Words: melanoma • senescence • tumor suppressor

Loss of tumor-suppressive pathways that control cellular senescence is a crucial step in malignant transformation. Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase that has been recently implicated in tumor suppression of melanoma, a deadly skin cancer derived from pigment-producing melanocytes. However, the mechanism by which Syk suppresses melanoma growth remains unclear. Here, we report that reexpression of Syk in melanoma cells induces a p53-dependent expression of the cyclin-dependent kinase (cdk) inhibitor p21 and a senescence program. We first observed that Syk expression is lost in a subset of melanoma cell lines, primarily by DNA methylation–mediated gene silencing and restored after treatment with the demethylating agent 5-aza-2-deoxycytidine. We analyzed the significance of epigenetic inactivation of Syk and found that reintroduction of Syk in melanoma cells dramatically reduces clonogenic survival and three-dimensional tumor spheroid growth and invasion. Remarkably, melanoma cells reexpressing Syk display hallmarks of senescent cells, including reduction of proliferative activity and DNA synthesis, large and flattened morphology, senescence-associated β-galactosidase activity, and heterochromatic foci. This phenotype is accompanied by hypophosphorylated retinoblastoma protein (Rb) and accumulation of p21, which depends on functional p53. Our results highlight a new role for Syk tyrosine kinase in regulating cellular senescence and identify Syk-mediated senescence as a novel tumor suppressor pathway the inactivation of which may contribute to melanoma tumorigenicity. [Cancer Res 2009;69(7):2748–56]

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