An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid

Marc de la Roche, Trevor J. Rutherford, Deepti Gupta, Dmitry B. Veprintsev, Barbara Saxty, Stefan M. Freund and Mariann Bienz ()
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Marc de la Roche: MRC Laboratory of Molecular Biology
Trevor J. Rutherford: MRC Laboratory of Molecular Biology
Deepti Gupta: MRC Laboratory of Molecular Biology
Dmitry B. Veprintsev: MRC Laboratory of Molecular Biology
Barbara Saxty: MRC Technology
Stefan M. Freund: MRC Laboratory of Molecular Biology
Mariann Bienz: MRC Laboratory of Molecular Biology

Nature Communications, 2012, vol. 3, issue 1, 1-10

Abstract: Abstract Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin.

Date: 2012
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DOI: 10.1038/ncomms1680

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