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PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation
Hae-Yun Jung1, Sohee Jun, Moonsup Lee
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Molecular Cell
|September 24, 2013
Summary
Poly(ADP-ribose) glycohydrolase (PAF) unexpectedly regulates Wnt signaling, a pathway crucial for development and implicated in cancer. Overexpressed PAF drives colon cancer proliferation by enhancing Wnt signaling and gene activation.
Area of Science:
- Molecular Biology
- Cancer Biology
- Developmental Biology
Background:
- Wnt signaling is vital for cellular processes and development.
- Dysregulated Wnt signaling is linked to cancer development.
- The role of translesion DNA synthesis components in Wnt signaling is largely unexplored.
Purpose of the Study:
- To investigate the function of Poly(ADP-ribose) glycohydrolase (PAF) in Wnt signaling.
- To elucidate the mechanism by which PAF modulates Wnt signaling.
- To determine the role of PAF in colon cancer and intestinal neoplasia.
Main Methods:
- Investigated PAF's role in Wnt signaling modulation using Xenopus laevis and mouse models.
- Analyzed PAF's interaction with PCNA and β-catenin upon Wnt activation.
- Examined PAF's recruitment of EZH2 to the β-catenin transcriptional complex.
- Assessed the impact of conditional PAF expression on intestinal tumorigenesis in mice.
Main Results:
- PAF is overexpressed in colon cancer cells and intestinal stem cells, promoting proliferation.
- PAF hyperactivates Wnt signaling in Xenopus, inducing secondary axis formation and target gene upregulation.
- PAF directly binds β-catenin and recruits EZH2, enhancing Wnt target gene transactivation.
- Conditional PAF expression in mice leads to intestinal neoplasia via Wnt pathway hyperactivation.
Conclusions:
- PAF plays a critical, previously unrecognized role in regulating Wnt signaling.
- PAF acts as a key modulator of Wnt signaling during tumorigenesis.
- PAF's interaction with the β-catenin complex provides a novel mechanism for Wnt pathway control.
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