Journal
NATURE COMMUNICATIONS
Volume 3, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms1680
Keywords
-
Categories
Funding
- Medical Research Council [U105192713]
- Cancer Research UK [C7379/A8709]
- Medical Research Council [MC_U105184273, MC_U105192713, MC_G1000806] Funding Source: researchfish
- MRC [MC_G1000806, MC_U105184273, MC_U105192713] Funding Source: UKRI
Ask authors/readers for more resources
Wnt/beta-catenin signalling controls development and tissue homeostasis. Moreover, activated beta-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic beta-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of beta-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional beta-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile alpha-helix (H1) amino-terminally abutting the BCL9-binding site in beta-catenin. Similarly, in colorectal cancer cells with hyperactive beta-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of beta-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of beta-catenin, which can be exploited for destabilization of oncogenic beta-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic beta-catenin.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available