Title

TRIB2 Acts Downstream of Wnt/TCF in Liver Cancer Cells to Regulate YAP and C/EBPalpha Function

UMMS Affiliation

Program in Gene Function and Expression; Department of Cancer Biology

Date

7-25-2013

Document Type

Article

Medical Subject Headings

Liver Neoplasms; Intracellular Signaling Peptides and Proteins; Wnt Signaling Pathway

Disciplines

Cancer Biology | Genetics and Genomics

Abstract

Dysregulation 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 betaTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPalpha-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/beta-catenin, Hippo/YAP, and C/EBPalpha pathways in cancer cells.

Rights and Permissions

Citation: Mol Cell. 2013 Jul 25;51(2):211-25. doi: 10.1016/j.molcel.2013.05.013. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

23769673