Hyun-A Kim1, Bon-Kyoung Koo1, Ji-Hoon Cho2, Yoon-Young Kim1,3, Jinwoo Seong1, Hee Jin Chang4, Young Min Oh3, Daniel E. Stange5, Jae-Gahb Park4, Daehee Hwang2 and Young-Yun Kong1,*
1Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
2School of Interdisciplinary Bioscience and Bioengineering, and
3Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
4Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
5Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Utrecht, The Netherlands.
*Address correspondence to: Young-Yun Kong, Department of Biological Sciences, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul, 151-747, Republic of Korea.
Authorship note: Hyun-A Kim and Bon-Kyoung Koo contributed equally to this work.
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.