Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Hyun-A Kim - , Seoul National University (Author)
  • Bon-Kyoung Koo - , Seoul National University (Author)
  • Ji-Hoon Cho - , Pohang University of Science and Technology (Author)
  • Yoon-Young Kim - , Seoul National University, Pohang University of Science and Technology (Author)
  • Jinwoo Seong - , Seoul National University (Author)
  • Hee Jin Chang - , National Cancer Center Korea (Author)
  • Young Min Oh - , Pohang University of Science and Technology (Author)
  • Daniel E. Stange - , Department of Visceral, Thoracic and Vascular Surgery, Utrecht University, Royal Netherlands Academy of Arts and Sciences, Hubrecht Inst KNAW (Author)
  • Jae-Gahb Park - , National Cancer Center Korea (Author)
  • Daehee Hwang - , Pohang University of Science and Technology (Author)
  • Young-Yun Kong - , Seoul National University (Author)

Abstract

Crosstalk between the Notch and wingless-type MMTV integration site (WNT) signaling pathways has been investigated for many developmental processes. However, this negative correlation between Notch and WNT/beta-catenin signaling activity has been studied. primarily in normal developmental and physiological processes in which negative feedback loops for both signaling pathways are intact. We found that Notch1 signaling retained the capability of suppressing the expression of WNT target genes in colorectal cancers even when beta-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apc(min) mouse colon cancer model and suppressed the expression of WNT target genes in human colorectal cancer cells through epigenetic modification recruiting histone methyltransferase SET domain bifurcated 1 (SETDB1). Extensive microarray analysis of human colorectal cancers also showed a negative correlation between the Notch1 target gene, Notch-regulated ankyrin repeat protein 1 (NRARP), and WNT target genes. Notch is known to be a strong promoter of tumor initiation, but here we uncovered an unexpected. suppressive role of Notch1 on WNT/beta-catenin target genes involved in colorectal cancer.

Details

Original languageEnglish
Pages (from-to)3248-3259
Number of pages12
JournalJournal of Clinical Investigation
Volume122
Issue number9
Publication statusPublished - Sept 2012
Peer-reviewedYes

External IDs

PubMed 22863622
Scopus 84865988309

Keywords

Keywords

  • Progenitor cells, Wnt, Gene, Expression, Pathways, Transcription, Methylation, Complex, Nrarp, Crypt