LATS2 Suppresses Oncogenic Wnt Signaling by Disrupting β-Catenin/BCL9 Interaction

• LATS2 is a nuclear repressor of Wnt/β-catenin-mediated transcription
• LATS2 inhibits oncogenic β-catenin signaling by disrupting the β-catenin/BCL9 complex
• LATS2 expression is inversely correlated with colorectal cancer development
• Nocodazole, an antimicrotubule drug, can inhibit β-catenin/BCL9 by inducing LATS2

SummaryAbnormal activation of Wnt/β-catenin-mediated transcription is associated with a variety of human cancers. Here, we report that LATS2 inhibits oncogenic Wnt/β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. LATS2 directly interacts with β-catenin and is present on Wnt target gene promoters. Mechanistically, LATS2 inhibits the interaction between BCL9 and β-catenin and subsequent recruitment of BCL9, independent of LATS2 kinase activity. LATS2 is downregulated and inversely correlated with the levels of Wnt target genes in human colorectal cancers. Moreover, nocodazole, an antimicrotubule drug, potently induces LATS2 to suppress tumor growth in vivo by targeting β-catenin/BCL9. Our results suggest that LATS2 is not only a key tumor suppressor in human cancer but may also be an important target for anticancer therapy.

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