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Aberrant activation of the Wnt/β-catenin signaling axis is a prominent oncogenic mechanism in numerous cancers including cervical cancer. Wnt inhibitory factor-1 (WIF1) is a secreted protein that binds Wnt and antagonizes Wnt activity. While theWIF1gene is characterized as a target for epigenetic silencing in some tumor types,WIF1expression has not been examined in human cervical tissue and cervical cancer. Here, we show thatWIF1is unmethylated and its gene product is expressed in normal cervical epithelium and some cultured cervical tumor lines. In contrast, several cervical cancer lines contained dense CpG methylation within theWIF1gene, and expression of both WIF1 transcript and protein was restored by culturing cells in the presence of the global DNA demethylating agent 5-aza-2′-deoxycytidine. Using single-molecule MAPit methylation footprinting, we observed differences in chromatin structure within theWIF1promoter region between cell lines that express and those that do not express WIF1, consistent with transcriptional activity and repression, respectively. TheWIF1promoter was aberrantly methylated in ∼60% (10 of 17) high-grade highly undifferentiated squamous cell cervical tumors examined, whereas paired normal tissue showed significantly lower levels of CpG methylation. WIF1 protein was not detectable by immunohistochemistry in tumors with quantitatively high levels ofWIF1methylation. Of note, WIF1 protein was not detectable in two of the seven unmethylated cervical tumors examined, suggesting other mechanisms may contribute WIF1 repression. Our findings establish theWIF1gene as a frequent target for epigenetic silencing in squamous cell carcinoma of the cervix.

WIF1 is a frequent target for epigenetic silencing in squamous cell carcinoma of the cervix