Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer

Wei Zhang, Sabine C. Glöckner, Mingzhou Guo, Emi Ota Machida, David H. Wang, Hariharan Easwaran, Leander Van Neste, James G. Herman, Kornel E. Schuebel, D. Neil Watkins, Nita Ahuja, Stephen B. Baylin

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2764-2772
Number of pages9
JournalCancer Research
Volume68
Issue number8
DOIs
StatePublished - Apr 15 2008

Fingerprint

Epigenomics
Colorectal Neoplasms
CpG Islands
Genes
Cell Line
Catenins
Wnt Signaling Pathway
Gene Silencing
Esophageal Neoplasms
Genetic Promoter Regions
Non-Small Cell Lung Carcinoma
Adenoma
Methylation
Interleukin-2
Carcinogenesis
Transcription Factors
Stem Cells
Gene Expression
DNA
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. / Zhang, Wei; Glöckner, Sabine C.; Guo, Mingzhou; Machida, Emi Ota; Wang, David H.; Easwaran, Hariharan; Van Neste, Leander; Herman, James G.; Schuebel, Kornel E.; Watkins, D. Neil; Ahuja, Nita; Baylin, Stephen B.

In: Cancer Research, Vol. 68, No. 8, 15.04.2008, p. 2764-2772.

Research output: Contribution to journalArticle

Zhang, W, Glöckner, SC, Guo, M, Machida, EO, Wang, DH, Easwaran, H, Van Neste, L, Herman, JG, Schuebel, KE, Watkins, DN, Ahuja, N & Baylin, SB 2008, 'Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer', Cancer Research, vol. 68, no. 8, pp. 2764-2772. https://doi.org/10.1158/0008-5472.CAN-07-6349
Zhang, Wei ; Glöckner, Sabine C. ; Guo, Mingzhou ; Machida, Emi Ota ; Wang, David H. ; Easwaran, Hariharan ; Van Neste, Leander ; Herman, James G. ; Schuebel, Kornel E. ; Watkins, D. Neil ; Ahuja, Nita ; Baylin, Stephen B. / Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. In: Cancer Research. 2008 ; Vol. 68, No. 8. pp. 2764-2772.
@article{49971fee47da4f5d99b38a4cc8f24938,
title = "Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer",
abstract = "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.",
author = "Wei Zhang and Gl{\"o}ckner, {Sabine C.} and Mingzhou Guo and Machida, {Emi Ota} and Wang, {David H.} and Hariharan Easwaran and {Van Neste}, Leander and Herman, {James G.} and Schuebel, {Kornel E.} and Watkins, {D. Neil} and Nita Ahuja and Baylin, {Stephen B.}",
year = "2008",
month = "4",
day = "15",
doi = "10.1158/0008-5472.CAN-07-6349",
language = "English (US)",
volume = "68",
pages = "2764--2772",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer

AU - Zhang, Wei

AU - Glöckner, Sabine C.

AU - Guo, Mingzhou

AU - Machida, Emi Ota

AU - Wang, David H.

AU - Easwaran, Hariharan

AU - Van Neste, Leander

AU - Herman, James G.

AU - Schuebel, Kornel E.

AU - Watkins, D. Neil

AU - Ahuja, Nita

AU - Baylin, Stephen B.

PY - 2008/4/15

Y1 - 2008/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=42349108108&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=42349108108&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-6349

DO - 10.1158/0008-5472.CAN-07-6349

M3 - Article

VL - 68

SP - 2764

EP - 2772

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 8

ER -