Sox17 encodes a HMG box transcription factor and has been implicated in oligodendrocyte development ( 3), vascular development ( 4), formation of definitive endoderm ( 5), and embryonic hematopoiesis ( 6).

Sox genes have been classified into seven groups based on their amino acid sequence and genomic organization, and Sox17, together with Sox7 and Sox18, belongs to Sox group F ( 2). There are at least 30 members of the Sox family expressed in many different cell types and tissues, and at multiple stages during development ( 2). The Sox gene family was first identified by virtue of its strong homology (>50%) to the high mobility group (HMG) box of the sex-determining gene SRY ( 1). Together, our studies suggest that SOX17 is a negative modulator of canonical Wnt signaling, and that SOX17 silencing due to promoter hypermethylation is an early event during tumorigenesis and may contribute to aberrant activation of Wnt signaling in CRC. Structure-based deletion analysis further shows the presence of a Wnt signaling repression domain in the SOX17 HMG box. Overexpression of SOX17 in HCT116 CRC cells inhibits colony growth and β-catenin/T-cell factor–dependent transcription. Here, we report that CpG island methylation-dependent silencing of SOX17 occurs in 100% of CRC cell lines, 86% of colorectal adenomas, 100% of stage I and II CRC, 89% of stage III CRC, 89% of primary esophageal cancer, and 50% of non–small cell lung cancer.

Our recent global analysis of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that SOX17 gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. SRY-box containing gene 17 ( Sox17) is a member of the high mobility group (HMG) transcription factor superfamily, which plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of Wnt pathway activity.

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