Journal
MOLECULAR CELL
Volume 52, Issue 2, Pages 193-205Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.08.028
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Funding
- Duncan Family Institute Research Program Grant
- University Cancer Foundation [IRG-08-061-01]
- American Association for Cancer Research Pancreatic Cancer Action Network [11-20-25-PARK]
- Center for Stem Cell and Developmental Biology Transformative Pilot Grant
- SPORE in Ovarian Cancer
- Mike Hogg Research
- National Institutes of Health through MD Anderson's Cancer Center [CA016672]
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Fine control of Wnt signaling is essential for various cellular and developmental decision-making processes. However, deregulation of Wnt signaling leads to pathological consequences, one of which is cancer. Here, we identify a function of PAF, a component of translesion DNA synthesis, in modulating Wnt signaling. PAF is specifically overexpressed in colon cancer cells and intestinal stem cells and is required for colon cancer cell proliferation. In Xenopus laevis, ventrovegetal expression of PAF hyperactivates Wnt signaling, developing a secondary axis with beta-catenin target gene upregulation. Upon Wnt signaling activation, PAF dissociates from PCNA and binds directly to beta-catenin. Then, PAF recruits EZH2 to the beta-catenin transcriptional complex and specifically enhances Wnt target gene transactivation, independently of EZH2's methyltransferase activity. In mice, conditional expression of PAF induces intestinal neoplasia via Wnt signaling hyperactivation. Our studies reveal an unexpected role of PAF in regulating Wnt signaling and propose a regulatory mechanism of Wnt signaling during tumorigenesis.
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