Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest. - Archive ouverte HAL Access content directly
Journal Articles Cancer Research Year : 2009

Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest.

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Abstract

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 beta-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.
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Dates and versions

inserm-00371643 , version 1 (08-03-2010)

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Olivier Bailet, Nina Fenouille, Patricia Abbe, Guillaume Robert, Stéphane Rocchi, et al.. Spleen tyrosine kinase functions as a tumor suppressor in melanoma cells by inducing senescence-like growth arrest.: Syk activates p53 signaling pathway. Cancer Research, 2009, 69 (7), pp.2748-56. ⟨10.1158/0008-5472.CAN-08-2690⟩. ⟨inserm-00371643⟩
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