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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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TRIB2 acts downstream of Wnt/TCF in liver cancer cells to regulate YAP and C/EBPα function

Jiayi Wang1, Joo-Seop Park, Yingying Wei

  • 1Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Molecular Cell
|June 18, 2013
PubMed

Insights

Tribbles homolog 2 (TRIB2) is a key Wnt target gene in liver cancer, promoting cancer cell survival. TRIB2 integrates Wnt, Hippo/YAP, and C/EBPα pathways, revealing a novel regulatory mechanism in liver tumorigenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Wnt signaling pathway dysregulation is a known driver of liver cancer.
  • Specific Wnt transcriptional programs and downstream targets in liver cancer are not fully elucidated.

Purpose of the Study:

  • To identify novel Wnt target genes and regulatory mechanisms in liver cancer.
  • To investigate the role of Tribbles homolog 2 (TRIB2) in liver tumorigenesis.

Main Methods:

  • Analysis of Wnt/TCF transcriptional targets in liver cancer cells.
  • Investigated the interaction between TRIB2, YAP, and beta-transducin repeat-containing protein (βTrCP).
  • Assessed the effect of TRIB2 on C/EBPα-mediated inhibition of YAP/TEAD activity.

Main Results:

  • Identified TRIB2 as a direct Wnt/TCF target gene, co-regulated by TCF and FoxA transcription factors.
  • Demonstrated that Wnt-TRIB2 signaling is essential for liver cancer cell survival and transformation.
  • Showed TRIB2 stabilizes YAP by interacting with βTrCP and relieves C/EBPα-mediated suppression of YAP/TEAD activity.

Conclusions:

  • TRIB2 acts as a crucial signaling nexus, integrating Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in liver cancer.
  • Uncovered a novel regulatory mechanism for Wnt transcriptional output in liver cancer.
  • Suggests TRIB2 as a potential therapeutic target in liver cancer.

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