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

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 pigmentproducing 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 B-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]

Correlation between ZAP‐70, phospho‐ZAP‐70, and phospho‐Syk expression in leukemic cells from patients with CLL

“…In this study, kinase-deficient Syk inhibited the tumor-suppressive potential of wildtype Syk indicating that its kinase activity was essential in mediating the antitumor effect. Recently, it has been found that Syk functions as a tumor suppressor in melanoma cells by inducing the p53-dependent expression of p21 cip1 (26). Our data suggest a similar mechanism may be operative in CLL cells.…”

Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis

“…14 SYK has been shown to downregulate the transcription of cell-cycle progressive genes, such as CCND1, CCNA1, AKT1, and FOSL1. 5,6,26 On the other hand, the re-expression of SYK has been demonstrated to induce a TP53-dependent accumulation of CDKN1A and a senescence-like growth arrest in melanoma cells. 6 However, we did not find significant differences in mRNA levels of CCND1 and CDKN1A in Huh7 cells with and without SYK induction (data not shown).…”

“…Recently, SYK expression has been demonstrated in numerous nonhematopoietic cells, and its downregulation has been shown to be involved in tumor formation and progression. [3][4][5][6] The transfection of SYK into an SYK-negative cancer cell line dramatically inhibited its cell growth, migration, and invasion. [3][4][5][6] Conversely, the knockdown of SYK in SYK-positive breast cancer cells increased proliferation and invasion.…”

“…[3][4][5][6] The transfection of SYK into an SYK-negative cancer cell line dramatically inhibited its cell growth, migration, and invasion. [3][4][5][6] Conversely, the knockdown of SYK in SYK-positive breast cancer cells increased proliferation and invasion. 7 Several researchers have also reported that the loss of SYK expression correlates with poor survival and tumor metastasis in patients with breast, 8 bladder, 9 liver, 10 pancreas, 5 or stomach cancer.…”

“…11 Epigenetic silencing through hypermethylation of promoter CpG islands has been proposed to be involved in the loss of SYK expression in these tumors. [3][4][5][6] Although SYK was shown to affect cell proliferation, motility, and invasion in several types of cancers, in HCC, its tumor suppressive activity and the molecular mechanisms of its effects remain to be clarified.…”