Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-11, Vol.76 (21), p.6278-6289
• Main Authors: Lim, Shen Kiat, Lu, Ssu Yi, Kang, Shin-Ae, Tan, Hock Jin, Li, Zilin, Adrian Wee, Zhen Ning, Guan, Jye Swei, Reddy Chichili, Vishnu Priyanka, Sivaraman, J, Putti, Thomas, Thike, Aye Aye, Tan, Puay Hoon, Sudol, Marius, Virshup, David M, Chan, Siew Wee, Hong, Wanjin, Lim, Yoon Pin
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - physiology; Animals; Breast Neoplasms - pathology; Cell Cycle Proteins; Cell Line, Tumor; ErbB Receptors - physiology; Female; Humans; Mice; Nuclear Proteins - metabolism; Proteasome Endopeptidase Complex - physiology; Repressor Proteins - physiology; Trans-Activators; Transcription Factors - metabolism; Tumor Suppressor Proteins - physiology; Ubiquitin-Protein Ligases - physiology; Wnt Signaling Pathway - physiology; Wnt3A Protein - physiology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-3537

Cross-talk between the Hippo and Wnt pathways has been implicated recently in breast cancer development, but key intersections have yet to be fully defined. Here we report that WBP2, a transcription coactivator that binds the Hippo pathway transcription factor YAP/TAZ, contributes to Wnt signaling and breast cancer pathogenesis. Clinically, overexpression of WBP2 in breast cancer specimens correlated with malignant progression and poor patient survival. In breast cancer cells, nuclear entry and interaction of WBP2 with β-catenin was stimulated by Wnt3A, thereby activating TCF-mediated transcription and driving malignant invasive character. Mechanistic investigations showed WBP2 levels were controlled by the E3 ligase ITCH, which bound and target WBP2 for ubiquitin-dependent proteasomal degradation. Accordingly, ITCH silencing could elevate WBP2 levels. Wnt signaling upregulated WBP2 by disrupting ITCH-WBP2 interactions via EGFR-mediated tyrosine phosphorylation of WBP2 and TAZ/YAP competitive binding. Conversely, ITCH-mediated downregulation of WBP2 inhibited TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis. We identified somatic mutations in ITCH, which impaired its ability to degrade WBP2 and to block its function in cancer, even while retaining binding capacity to WBP2. Thus, the Wnt pathway appeared to engage WBP2 primarily by affecting its protein stability. Our findings show how WBP2/ITCH signaling functions to link the intricate Wnt and Hippo signaling networks in breast cancer. Cancer Res; 76(21); 6278-89. ©2016 AACR.