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Identification of Wnt-regulated genes that are repressed by, or independent of, β-catenin

Shiyang Liu1,2, Sara Haghani3, Enrico Petretto2,4

  • 1Program in Cancer and Stem Cell Biology, Duke-NUS School of Medicine, Singapore.

The FEBS Journal
|January 28, 2026
PubMed

Insights

Wnt signaling controls gene expression via β-catenin, but also independently. This study reveals 10% of Wnt-regulated genes are β-catenin-independent, often repressed, and identifies a negative regulatory element (NRE) involved in Wnt repression.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Biology

Background:

  • Wnt signaling is crucial for development and homeostasis, regulating genes through β-catenin.
  • A subset of Wnt-regulated genes are controlled independently of β-catenin, representing a less understood aspect of this pathway.
  • Understanding both arms of Wnt signaling is vital, particularly in cancer where it is often dysregulated.

Purpose of the Study:

  • To comprehensively analyze the β-catenin-dependent and independent components of Wnt signaling.
  • To identify genes regulated by Wnt signaling independently of β-catenin in a cancer model.
  • To investigate the mechanisms underlying Wnt/β-catenin-mediated gene repression.

Main Methods:

  • Utilized a pan-Wnt inhibitor to block Wnt signaling.
  • Performed comprehensive transcriptome analysis in a Wnt-addicted orthotopic cancer model.
  • Analyzed gene expression data to delineate β-catenin-dependent and independent regulation.

Main Results:

  • Identified that 10% of Wnt-regulated genes are controlled independently of β-catenin.
  • Found a significant proportion of β-catenin-independent genes are Wnt-repressed.
  • Discovered that the negative regulatory element (NRE) motif is enriched in promoters of β-catenin-repressed genes and is essential for repression.

Conclusions:

  • Provides a detailed characterization of the β-catenin-independent Wnt signaling pathway in cancer.
  • Suggests a cis-regulatory grammar dictates Wnt-dependent gene activation versus repression.
  • Highlights the NRE motif as a key player in Wnt-mediated gene repression.
Keywords:
PORCNWnt signalingpancreatic cancerrepressiontranscriptional regulationβ‐catenin

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