Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer
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
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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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 8

Notch signaling regulated expression of WNT target genes through epigenetic modification in CRCLs.

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Notch signaling regulated expression of WNT target genes through epigene...
(A and B) ChIP and PCR analysis of promoter regions of WNT target genes in Nrarphi LOVO cells and Nrarplo/– SW620 cells, and LOVO cells transfected with 2 εg of mock and DN-MAML (right panels) were treated for 96 hours. SW620 cells were transfected with 2 εg of mock vector or ΔEN1 for 48 hours. Soluble chromatin prepared from each cultured cells was immunoprecipitated with indicated Abs. The final DNA extracts were amplified using pairs of primers that cover the WNT/β-catenin–binding sites in promoter regions of WNT target genes. The exon 6 of GAPDH served as negative controls. (C and D) Real-time qRT-PCR analysis of WNT target genes (PROX1, c-MYC, and Axin2) in Nrarplo/– SW620 cells transfected with control siRNA, NLK siRNA, SETDB1 siRNA, mock vector (white bars), and ΔEN1 (black bars), as indicated. Levels of NLK, SETDB1, PROX1, Axin2, and c-MYC transcripts were measured after 48 hours. (E) ChIP analysis of WNT target genes (PROX1, c-MYC, and Axin2) in Nrarplo/– SW620 cells. SW620 cells were transfected with 2 εg of mock vector or ΔEN1 for 48 hours. Soluble chromatin prepared from each cultured cells was immunoprecipitated with indicated Abs. The final DNA extracts were amplified using pairs of primers that cover the WNT/β-catenin binding sites in promoter regions of WNT target genes. The exon 6 of GAPDH served as a negative control.