title: LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors.
abstract: Hyperactive β-catenin drives colorectal cancer, yet inhibiting its activity remains a formidable challenge. Interest is mounting in tankyrase inhibitors (TNKSi), which destabilize β-catenin through stabilizing Axin. Here, we confirm that TNKSi inhibit Wnt-induced transcription, similarly to carnosate, which reduces the transcriptional activity of β-catenin by blocking its binding to BCL9, and attenuates intestinal tumors in Apc(Min) mice. By contrast, β-catenin's activity is unresponsive to TNKSi in colorectal cancer cells and in cells after prolonged Wnt stimulation. This TNKSi insensitivity is conferred by β-catenin's association with LEF1 and BCL9-2/B9L, which accumulate during Wnt stimulation, thereby providing a feed-forward loop that converts transient into chronic β-catenin signaling. This limits the therapeutic value of TNKSi in colorectal carcinomas, most of which express high LEF1 levels. Our study provides proof-of-concept that the successful inhibition of oncogenic β-catenin in colorectal cancer requires the targeting of its interaction with LEF1 and/or BCL9/B9L, as exemplified by carnosate.
authors.affiliation: Authors' Affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge, United Kingdom.
authors.forename: Marc
authors.initials: M
authors.lastname: de la Roche
authors.forename: Ashraf E K
authors.initials: AE
authors.lastname: Ibrahim
authors.forename: Juliusz
authors.initials: J
authors.lastname: Mieszczanek
authors.forename: Mariann
authors.initials: M
authors.lastname: Bienz
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000235:genetics; D038501:Tankyrases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D051176:beta Catenin / Q000235:genetics*
chemical_list: D060466:Axin Protein; C495498:BCL9L protein, human; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D038501:Tankyrases