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Mol Cell 2013 Oct 24;522:193-205. doi: 10.1016/j.molcel.2013.08.028.
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PAF and EZH2 induce Wnt/β-catenin signaling hyperactivation.

Jung HY , Jun S , Lee M , Kim HC , Wang X , Ji H , McCrea PD , Park JI .

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 β-catenin target gene upregulation. Upon Wnt signaling activation, PAF dissociates from PCNA and binds directly to β-catenin. Then, PAF recruits EZH2 to the β-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.

PubMed ID: 24055345
PMC ID: PMC4040269
Article link: Mol Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ctnnb1 ezh2 pafah1b2 pcna

References [+] :
Ahn, BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb. 2001, Pubmed