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

作者：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^*

来源：Journal of Clinical Investigation, 2012, 122(9): 3248-3259.

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/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.

• 出版日期2012-9