The Wnt inhibitory factor 1 (WIF1) is targeted in glioblastoma and has a tumor suppressing function potentially by induction of senescence

Abstract

Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling. Ectopic expression of WIF1 in glioblastoma cell lines revealed a dose-dependent decrease of Wnt pathway activity. Furthermore, WIF1 expression inhibited cell proliferation in vitro, reduced anchorage-independent growth in soft agar, and completely abolished tumorigenicity in vivo. Interestingly, WIF1 overexpression in glioblastoma cells induced a senescence-like phenotype that was dose dependent. These results provide evidence that WIF1 has tumor suppressing properties. Downregulation of WIF1 in 75% of glioblastomas indicates frequent involvement of aberrant Wnt signaling and, hence, may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.

Promoter methylation of WNT inhibitory factor-1 and expression pattern of WNT/β-catenin pathway in human astrocytoma: pathologic and prognostic correlations

“…7,8 Our study also revealed an inverse correlation between promoter methylation and WIF1 protein expression, and an increase in WIF1 mRNA and protein expression level following demethylation treatment, confirming that promoter methylation is a major inactivation mechanism of the WIF1 gene.…”

“…19 The main mechanism of WIF1 inactivation is aberrant promoter methylation, as demonstrated by the inverse correlation between WIF1 promoter methylation and expression of WIF1 mRNA or protein 8,11,12,[19][20][21][22][23][24] and restoration of WIF1 expression by promoter demethylation treatment. 9,20,22, 23 Yang et al 7 first described WIF1 gene promoter hypermethylation in human astrocytoma and showed that this methylation was associated with decreased Wif1 mRNA and protein expression.…”

“…An inverse correlation between promoter methylation of the WIF1 gene and expression of WIF1 mRNA or protein 8,11,12,19,20,[22][23][24] and restoration of WIF1 expression by promoter demethylation treatment 9,20,22,23 have been shown in many malignant tumors including astrocytoma. 7,8 Our study also revealed an inverse correlation between promoter methylation and WIF1 protein expression, and an increase in WIF1 mRNA and protein expression level following demethylation treatment, confirming that promoter methylation is a major inactivation mechanism of the WIF1 gene.…”

“…It seems that astrocytomas with decreased WIF1 protein expression show worse prognosis because tumors with low WIF1 protein expression are more frequently high-grade tumors. A recent study 8 with glioblastoma cell line revealed that WIF1 overexpression induced a senescence-like phenotype, inhibited cell proliferation and anchorageindependent growth in vitro, and abolished tumorigenicity in vivo, suggesting that WIF1 can be a therapeutic target in the treatment of astrocytoma. Therefore, the independent prognostic effect of WIF1 promoter methylation and WIF1 protein expression is yet to be revealed with larger numbers of tumor samples.…”

“…Downregulation of WIF1 mRNA and protein expression levels as a result of WIF1 gene promoter methylation has been reported in human astrocytoma. 7,8 However, the influence of WIF1 promoter methylation and WIF1 protein expression level on components of WNT pathway has not been described in astrocytoma, except for a single study revealing that demethylation of the WIF1 gene promoter and restoration of WIF1 protein expression decreased cytosolic b-catenin protein levels. 9 Furthermore, although there is a published study on the relationship between WIF1 promoter methylation and the grade of astrocytomas, 7 the prognostic impact of WIF1 promoter methylation and WIF1 protein expression has not been investigated in astrocytomas.…”