Disease relevance of WIF1

• Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors) [1].
• Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1) [1].
• Our findings establish the WIF1 gene as a target for epigenetic silencing in breast cancer and provide a mechanistic link between the dysregulation of Wnt signaling and breast tumorigenesis [2].
• To our knowledge, this is the first report suggesting that WIF1 is a recurrent target in human salivary gland oncogenesis and that downregulation of WIF1 plays a role in the development and/or progression of pleomorphic adenomas [3].
• We screened 13 additional benign and malignant salivary gland tumors and detected WIF1 rearrangement in one out of two carcinomas ex-pleomorphic adenoma analyzed [3].

High impact information on WIF1

• This silencing also correlates with WIF-1 promoter methylation [4].
• Recently, down-regulation of WIF-1 has been reported in several human cancers [4].
• To discover the mechanism of WIF-1 silencing in lung cancer, we first identified the human WIF-1 promoter and subsequently examined the methylation status in the CpG islands [4].
• By using methylation-specific PCR and sequence analysis after bisulfite treatment, we demonstrate here frequent CpG island hypermethylation in the functional WIF-1 promoter region [4].
• Moreover, treatment with 5-aza-2'-deoxycytidine restores WIF-1 expression [4].

Chemical compound and disease context of WIF1

• We show that cultured human breast tumor cell lines display absent or low levels of WIF1 expression that are increased when cells are cultured with the DNA demethylating agent 5-aza-2'-deoxycytidine [2].

Biological context of WIF1

• We mapped the state of methylation of three of these genes, MELANOMA ANTIGEN B2 GENE (MAGEB2), METALLOPROTEINASE 2 (MMP2) and WIF1, which are involved in tumor growth and metastasis [5].
• These data suggest a possible synergistic effect between upregulation of HMGA2 and downregulation of WIF1 [3].
• In this malignant tumor, the rearrangement of one WIF1 allele coexists with loss of the other allele, a classic signature of a tumor suppressor gene [3].
• Transfection of the WIF-1 gene construct into TE-1 esophageal cancer cell lines or SW48 colon cancer cell lines lacking WIF-1 expression resulted in a significant inhibition on colony formation, cell proliferation, anchorage-independent growth in soft agar [6].
• In addition, known targets of the canonical Wnt/beta-catenin signaling pathway, such as c-myc and cyclin D1, were up-regulated in bladder tumor compared with bladder mucosa, and this up-regulation was associated with reduced Wif-1 expression at both mRNA and protein levels [7].

Anatomical context of WIF1

• WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors [3].
• By using RT-PCR, bisulfite sequence analysis, and methylation-specific PCR, we analysed expression and methylation of WIF-1 in cancer cell lines and freshly resected cancer tissues of the esophagus, stomach, colorectum, and pancreas [6].
• In the total bladder tumor and bladder mucosa samples, an inverse correlation was found between promoter methylation and Wif-1 mRNA transcript levels [7].
• Wnt inhibitory factor-1 (WIF-1) is a secreted antagonist of Wnt signaling and acts through direct binding to Wnt in the extracellular space [8].
• In this study, we revealed downregulated WIF-1 expression in cell lines and primary tissue when compared to normal mesothelial cell lines and adjacent pleura, respectively [9].

Associations of WIF1 with chemical compounds

• Furthermore, the WIF1 promoter is aberrantly hypermethylated in these cells as judged by both methylation-specific PCR and bisulfite genomic sequencing [2].
• Treatment with demethylating agent, 5-aza-2'-deoxycytidine (5-aza-dC), restored WIF-1 expression in cancer cell lines [6].
• A combined treatment of 5-aza-dC and a histone deacetylase inhibitor, trichostatinA, restored WIF-1 expression synergistically, indicating the role of cytosine methylation and histone deacetylation in the silencing of the WIF-1 gene [6].
• The PI3K inhibitor LY294002 seemed to restore the chemosensitivity of native PC-3 cells like WIF-1 did [10].

Regulatory relationships of WIF1

• In the present study, we found that WIF-1 downregulates the Akt pathway and also enhances chemosensitivity in PTEN-null Pca cells [10].
• In normal salivary gland tissue WIF1 is expressed at a high level and HMGA2 is not expressed [3].

Other interactions of WIF1

• Some tumors showed concomitant APC, sFRP1 and WIF-1 gene inactivation, indicating that multiple DNA methylation events must have occurred to definitively down-regulate the signaling through Wnt [11].
• Epigenetic inactivation of Wnt inhibitory factor-1 plays an important role in bladder cancer through aberrant canonical Wnt/beta-catenin signaling pathway [7].
• CpG island hypermethylation in the WIF-1 promoter region correlated with downregulation of WIF-1 expression in cancer cell lines and tissues [6].
• Preferential methylation of Wnt inhibitory factor-1 in acute promyelocytic leukemia: an independent poor prognostic factor [12].

References