Journal Article

IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype

Hiromu Suzuki, Shinichi Igarashi, Masanori Nojima, Reo Maruyama, Eiichiro Yamamoto, Masahiro Kai, Hirofumi Akashi, Yoshiyuki Watanabe, Hiroyuki Yamamoto, Yasushi Sasaki, Fumio Itoh, Kohzoh Imai, Tamotsu Sugai, Lanlan Shen, Jean-Pierre J. Issa, Yasuhisa Shinomura, Takashi Tokino and Minoru Toyota

in Carcinogenesis

Volume 31, issue 3, pages 342-349
Published in print March 2010 | ISSN: 0143-3334
Published online July 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp179
IGFBP7 is a p53-responsive gene specifically silenced in colorectal cancer with CpG island methylator phenotype

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

A subset of colorectal cancers (CRCs) show simultaneous methylation of multiple genes; these tumors have the CpG island methylator phenotype (CIMP). CRCs with CIMP show a specific pattern of genetic alterations, including a high frequency of BRAF mutations and a low frequency of p53 mutations. We therefore hypothesized that genes inactivated by DNA methylation are involved in the BRAF- and p53-signaling pathways. Among those, we examined the epigenetic inactivation of insulin-like growth factor-binding protein 7 (IGFBP7) expression in CRCs. We found that in CRC cell lines, the silencing of IGFBP7 expression was correlated with high levels of DNA methylation and low levels of histone H3K4 methylation. Luciferase and chromatin immunoprecipitation assays in unmethylated cells revealed that p53 induces expression of IGFBP7 upon binding to a p53 response element within intron 1 of the gene. Treating methylated CRC cell lines with 5-aza-2′-deoxycytidine restored p53-induced IGFBP7 expression. Levels of IGFBP7 methylation were also significantly higher in primary CRC specimens than in normal colonic tissue (P < 0.001). Methylation of IGFBP7 was correlated with BRAF mutations, an absence of p53 mutations and the presence of CIMP. Thus, epigenetic inactivation of IGFBP7 appears to play a key role in tumorigenesis of CRCs with CIMP by enabling escape from p53-induced senescence.

Journal Article.  5272 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.