This Article Full Text Full Text (PDF) Correction (v68,p6030) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, W. Articles by Baylin, S. B. Search for Related Content PubMed PubMed Citation Articles by Zhang, W. Articles by Baylin, S. B.

Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal Cancer

¹ Division of Cancer Biology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University; ² Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ³ Department of Gastroenterology, Chinese PLA General Hospital, Beijing, China; and ⁴ Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium

Requests for reprints: Stephen B. Baylin, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231. Phone: 410-955-8506; Fax: 410-614-9884; E-mail: sbaylin{at}jhmi.edu.

Key Words: SOX17 • hypermethylation • Wnt signaling • 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 β-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. [Cancer Res 2008;68(8):2764–72]

This article has been cited by other articles:

				Y. Ye, M. A. McDevitt, M. Guo, W. Zhang, O. Galm, S. D. Gore, J. E. Karp, J. P. Maciejewski, J. Kowalski, H.-L. Tsai, et al. Progressive Chromatin Repression and Promoter Methylation of CTNNA1 Associated with Advanced Myeloid Malignancies Cancer Res., November 1, 2009; 69(21): 8482 - 8490. [Abstract] [Full Text] [PDF]

				H. Dopeso, S. Mateo-Lozano, R. Mazzolini, P. Rodrigues, L. Lagares-Tena, J. Ceron, J. Romero, M. Esteves, S. Landolfi, J. Hernandez-Losa, et al. The Receptor Tyrosine Kinase EPHB4 Has Tumor Suppressor Activities in Intestinal Tumorigenesis Cancer Res., September 15, 2009; 69(18): 7430 - 7438. [Abstract] [Full Text] [PDF]

				H. P. Mohammad, Y. Cai, K. M. McGarvey, H. Easwaran, L. Van Neste, J. E. Ohm, H. M. O'Hagan, and S. B. Baylin Polycomb CBX7 Promotes Initiation of Heritable Repression of Genes Frequently Silenced with Cancer-Specific DNA Hypermethylation Cancer Res., August 1, 2009; 69(15): 6322 - 6330. [Abstract] [Full Text] [PDF]

				M. A. Hahn, T. Hahn, D.-H. Lee, R. S. Esworthy, B.-w. Kim, A. D. Riggs, F.-F. Chu, and G. P. Pfeifer Methylation of Polycomb Target Genes in Intestinal Cancer Is Mediated by Inflammation Cancer Res., December 15, 2008; 68(24): 10280 - 10289. [Abstract] [Full Text] [PDF]

				J. M. Yi, H.-C. Tsai, S. C. Glockner, S. Lin, J. E. Ohm, H. Easwaran, C. D. James, J. F. Costello, G. Riggins, C. G. Eberhart, et al. Abnormal DNA Methylation of CD133 in Colorectal and Glioblastoma Tumors Cancer Res., October 1, 2008; 68(19): 8094 - 8103. [Abstract] [Full Text] [PDF]

				Correction: Hypermethylation of Wnt Antagonist SOX17 in Colorectal Cancer Cancer Res., July 15, 2008; 68(14): 6030 - 6030. [Full Text] [PDF]