Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer
Hyun-A Kim, … , Daehee Hwang, Young-Yun Kong
Hyun-A Kim, … , Daehee Hwang, Young-Yun Kong
Published August 6, 2012
Citation Information: J Clin Invest. 2012;122(9):3248-3259. https://doi.org/10.1172/JCI61216.
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Research Article Oncology

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

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/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.

Authors

Hyun-A Kim, Bon-Kyoung Koo, Ji-Hoon Cho, Yoon-Young Kim, Jinwoo Seong, Hee Jin Chang, Young Min Oh, Daniel E. Stange, Jae-Gahb Park, Daehee Hwang, Young-Yun Kong

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Figure 2

Decreased levels of WNT target genes in Notch-activated Apcmin tumors.

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Decreased levels of WNT target genes in Notch-activated Apcmin tumors. ...
Colons (normal) from 10-week-old WT and 7-week-old Vil-Cre;RosaN1+/RN1 (N1) mice and colonic tumor tissues (tumor) from 10-week-old Apcmin (APC) and 7-week-old Vil-Cre;RosaN1+/RN1;Apcmin mice were used for gene expression and histological analysis. (A) Heat map of gene expression levels. Clusters A and B indicate genes that reverted to levels in normal tissues upon Notch activation in the tumors. (B–E) Real-time qRT-PCR analysis (B–E). Note the reduced expression levels of WNT target genes (Axin2, Wif1, Nkd1, and Apcdd1) in APC;N1 tumors compared with those of APC tumors. Bars indicate mean + SD. *P < 0.05; **P < 0.01; ***P < 0.001. (F and G) In situ hybridization (F) and fluorescent immunostaining (G) of Apcmin (upper panels) and Vil-Cre;RosaN1+/RN1;Apcmin (lower panels) tumors. Note that the expression levels of Axin2, Wif1, Apcdd1, and PROX1 were reduced or absent in Vil-Cre;RosaN1+/RN1;Apcmin tumors. Dotted lines indicate tumor regions. Scale bars: 100 εm (F); 50 εm (G).