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

• Published in: The Journal of clinical investigation 2012-09, Vol.122 (9), p.3248-3259
• Main Authors: Kim, Hyun-A, Koo, Bon-Kyoung, Cho, Ji-Hoon, Kim, Yoon-Young, Seong, Jinwoo, Chang, Hee Jin, Oh, Young Min, Stange, Daniel E, Park, Jae-Gahb, Hwang, Daehee, Kong, Young-Yun
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - metabolism; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenoma - metabolism; Adenoma - pathology; Adenomatous Polyposis Coli Protein - deficiency; Adenomatous Polyposis Coli Protein - genetics; Analysis of Variance; Animals; beta Catenin - metabolism; Care and treatment; CDX2 Transcription Factor; Cell Line, Tumor; Cellular signal transduction; Chromatin; Chromatin - metabolism; Colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Diagnosis; Gene Expression Regulation, Neoplastic; Genetic aspects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Kaplan-Meier Estimate; Mice; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Properties; Protein Methyltransferases - metabolism; Protein-Serine-Threonine Kinases - metabolism; Receptor, Notch1 - metabolism; Transcriptome; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vimentin - genetics; Vimentin - metabolism; Wnt Proteins - metabolism; Wnt Signaling Pathway
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI61216

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/β-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 β-catenin destruction by the adenomatous polyposis coli (APC) complex was disabled. Activation of Notch1 converted high-grade adenoma into low-grade adenoma in an Apcmin 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/β-catenin target genes involved in colorectal cancer.