Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer.
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. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. 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. 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. Overexpression of SOX17 in HCT116 CRC cells inhibits colony growth and beta-catenin/T-cell factor-dependent transcription. Structure-based deletion analysis further shows the presence of a Wnt signaling repression domain in the SOX17 HMG box. 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.
Zhang
Wei
W
Division of Cancer Biology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA.
Glöckner
Sabine C
SC
Guo
Mingzhou
M
Machida
Emi Ota
EO
Wang
David H
DH
Easwaran
Hariharan
H
Van Neste
Leander
L
Herman
James G
JG
Schuebel
Kornel E
KE
Watkins
D Neil
DN
Ahuja
Nita
N
Baylin
Stephen B
SB
D002460:Cell Line; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D020868:Gene Silencing; D017930:Genes, Reporter; D024282:Genes, sry; D005822:Genetic Vectors; D006609:High Mobility Group Proteins / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000196:embryology; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D055760:SOXF Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D012334:RNA, Neoplasm; C109188:SOX17 protein, human; D055760:SOXF Transcription Factors; D014157:Transcription Factors