| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1996480 | Molecular Cell | 2013 | 15 Pages |
•Screen identifies TRIB2 as a critical Wnt/TCF target and effector in liver cancer•Liver cancer cell-specific Wnt transcriptional output is regulated by FoxA1/2•TRIB2 promotes YAP stabilization through interaction with the E3 ligase βTrCP•TRIB2 relieves C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation
SummaryDysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.
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