title: An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid.
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.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: de la Roche
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Deepti
authors.initials: D
authors.lastname: Gupta
authors.forename: Dmitry B
authors.initials: DB
authors.lastname: Veprintsev
authors.forename: Barbara
authors.initials: B
authors.lastname: Saxty
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Freund
authors.forename: Mariann
authors.initials: M
authors.lastname: Bienz
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010936:Plant Extracts / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D027542:Rosmarinus; D015398:Signal Transduction; D014157:Transcription Factors; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D045784:Abietanes; C111180:BCL9 protein, human; D009363:Neoplasm Proteins; D010936:Plant Extracts; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex; C018381:salvin