Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling.

Deregulated Wnt/beta-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of beta-catenin with B cell lymphoma 9 (BCL9), a coactivator for beta-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives beta-catenin signaling through direct binding mediated by its alpha-helical homology domain 2. We developed a stabilized a helix of BCL9 (SAH-BCL9), which we show targets beta-catenin, dissociates native beta-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-beta-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.