Selective dissociation of BCL9–β-catenin complexes suppresses WNT-driven tumorigenesis.

  • Major finding: Selective dissociation of BCL9–β-catenin complexes suppresses WNT-driven tumorigenesis.

  • Approach: A stapled peptide of BCL9 was used to inhibit pathologic β-catenin activity.

  • Impact: This approach may be clinically effective in treating cancers with dysregulated WNT signaling.

WNT signaling plays an important role in development and stem cell homeostasis, and mutations in this pathway have been implicated in multiple cancers. WNT activity is mediated via downstream β-catenin–regulated transcription, but previous attempts to target β-catenin in cancer have been largely unsuccessful due to toxic effects in normal tissues. Takada and colleagues investigated whether targeting β-catenin by harnessing its interface with BCL9, a coactivator that enhances β-catenin activity and is highly expressed in tumors compared with normal cells, could effectively suppress oncogenic WNT signaling. Hydrocarbon stapling was used to generate a cell-permeable peptide representing the domain of BCL9 that binds to a unique site on β-catenin. This stabilized α-helix of BCL9 (SAH-BCL9) was efficiently taken up by cells, localized to the nucleus, and interacted with β-catenin to disrupt BCL9–β-catenin complexes in colorectal carcinoma and multiple myeloma cells. Dissociation of these complexes resulted in reduced β-catenin–dependent transcription and downregulation of WNT target genes involved in proliferation, metastasis, and angiogenesis, suggesting that SAH-BCL9 might have antitumor activity. Indeed, treatment with this peptide decreased cancer cell proliferation, angiogenesis, and invasion in vitro. These effects were specific to tumor cells expressing BCL9 and were not observed with a control peptide in which a key binding residue was mutated; SAH-BCL9 also did not affect the interaction of β-catenin with other proteins such as E-cadherin. Furthermore, administration of SAH-BCL9 significantly impaired colorectal cancer and multiple myeloma xenograft growth and metastasis, diminished intratumoral blood vessel formation, and promoted tumor cell apoptosis. These results identify a strategy to selectively inhibit WNT–β-catenin signaling and suggest that this targeted approach may provide therapeutic benefit in cancers that are dependent on aberrant WNT activity.

Takada K, Zhu D, Bird GH, Sukhdeo K, Zhao JJ, Mani M, et al. Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Sci Transl Med 2012;4:148ra117.

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