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• W2024006296 abstract "In this issue of Molecular Cell, Park and colleagues (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) show that PAF (PCNA-associated factor) binds to and hyperactivates transcriptional function of β-catenin in colon cancer cells by recruiting EZH2 to the coactivator complex. PAF-β-catenin and PAF-PCNA interactions are competitive, raising the question of whether β-catenin might regulate PCNA-dependent DNA replication and repair. In this issue of Molecular Cell, Park and colleagues (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar) show that PAF (PCNA-associated factor) binds to and hyperactivates transcriptional function of β-catenin in colon cancer cells by recruiting EZH2 to the coactivator complex. PAF-β-catenin and PAF-PCNA interactions are competitive, raising the question of whether β-catenin might regulate PCNA-dependent DNA replication and repair. Wnt signaling through stabilization of transcription coactivator β-catenin plays critical roles in animal development and tissue homeostasis, and its deregulation is involved in myriad human diseases including cancer (Clevers and Nusse, 2012Clevers H. Nusse R. Cell. 2012; 149: 1192-1205Abstract Full Text Full Text PDF PubMed Scopus (3986) Google Scholar). Notably, most colorectal cancers (CRCs) have elevated β-catenin signaling caused by mutations of Wnt pathway components such as the tumor suppressor APC (Adenomatosis polyposis coli) and β-catenin itself (Clevers and Nusse, 2012Clevers H. Nusse R. Cell. 2012; 149: 1192-1205Abstract Full Text Full Text PDF PubMed Scopus (3986) Google Scholar). Much effort has focused on studying β-catenin-dependent transactivation in CRCs, including the current study by Park and colleagues that identifies PAF as an unexpected β-catenin coactivator (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). PAF, for PCNA (proliferating cell nuclear antigen)-associated factor (also known as KIAA0101 or p15PAF), is an interacting partner of PCNA (Yu et al., 2001Yu P. Huang B. Shen M. Lau C. Chan E. Michel J. Xiong Y. Payan D.G. Luo Y. Oncogene. 2001; 20: 484-489Crossref PubMed Scopus (88) Google Scholar). PCNA has a key role in DNA replication and repair by assembling various DNA polymerase and repair complexes at the replication fork (Mailand et al., 2013Mailand N. Gibbs-Seymour I. Bekker-Jensen S. Nat. Rev. Mol. Cell Biol. 2013; 14: 269-282Crossref PubMed Scopus (257) Google Scholar). Dynamic regulation of PAF abundance and/or interaction with PCNA appears to be important for engaging DNA damage repair and bypass pathways (Emanuele et al., 2011Emanuele M.J. Ciccia A. Elia A.E. Elledge S.J. Proc. Natl. Acad. Sci. USA. 2011; 108: 9845-9850Crossref PubMed Scopus (82) Google Scholar, Povlsen et al., 2012Povlsen L.K. Beli P. Wagner S.A. Poulsen S.L. Sylvestersen K.B. Poulsen J.W. Nielsen M.L. Bekker-Jensen S. Mailand N. Choudhary C. Nat. Cell Biol. 2012; 14: 1089-1098Crossref PubMed Scopus (196) Google Scholar). PAF is overexpressed in many types of cancers and required for cell proliferation (e.g., Yu et al., 2001Yu P. Huang B. Shen M. Lau C. Chan E. Michel J. Xiong Y. Payan D.G. Luo Y. Oncogene. 2001; 20: 484-489Crossref PubMed Scopus (88) Google Scholar). In the current study (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar), Jung et al. show that PAF is overexpressed in CRCs in a manner that parallels expression of Axin2, an established Wnt/β-catenin target gene. PAF knockdown inhibits CRC proliferation, and this effect is independent of PAF-PCNA interaction and can be rescued by a PAF mutant that does not bind to PCNA or by β-catenin overexpression. PAF knockdown downregulates the expression of Wnt/β-catenin target genes Cyclin D1, c-Myc, and Axin2 in a CRC line, leading the authors to hypothesize that PAF participates in Wnt/β-catenin signaling. Indeed, PAF knockdown reduces and its overexpression augments Wnt/β-catenin-responsive TOPFLASH reporter and target gene expression induced by Wnt3a or by pharmacological agents that stabilize β-catenin. In Xenopus embryos, PAF synergizes with β-catenin to induce Wnt target gene expression and axis duplication (a hallmark of Wnt/β-catenin activation). In mouse embryos, PAF is highly expressed in regions known for Wnt/β-catenin signaling such as the apical ectodermal ridge of the limb bud. Therefore, PAF appears to be a positive regulator of Wnt/β-catenin signaling in CRCs and vertebrate embryos. PAF does not affect β-catenin protein levels and is localized in the nucleus. Protein binding assays show that PAF interacts, directly or indirectly, with β-catenin (via the armadillo-repeat domain) and its DNA-bound partner TCF (T cell factor). Indeed PAF is associated with promoters of Wnt/β-catenin target genes in chromatin in CRC cells. Interestingly in the mouse intestine, the PAF protein is enriched in Bmi (B lymphoma Mo-MLV insertion region 1 homolog)-positive stem cells (at the “+4” position) (Sangiorgi and Capecchi, 2008Sangiorgi E. Capecchi M.R. Nat. Genet. 2008; 40: 915-920Crossref PubMed Scopus (964) Google Scholar). Bmi1 is a component of polycomb repressive complex 1 (PRC1), which, together with the PRC2 complex that modifies histone H3, has critical functions in transcriptional epigenetic silencing. Previous studies have suggested that a core PRC2 component, EZH2 (enhancer of zeste homolog 2), is a partner and paradoxically a coactivator of β-catenin, acting in a manner that is independent of EZH2’s methyltransferase activity (Li et al., 2009Li X. Gonzalez M.E. Toy K. Filzen T. Merajver S.D. Kleer C.G. Am. J. Pathol. 2009; 175: 1246-1254Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Shi et al., 2007Shi B. Liang J. Yang X. Wang Y. Zhao Y. Wu H. Sun L. Zhang Y. Chen Y. Li R. et al.Mol. Cell. Biol. 2007; 27: 5105-5119Crossref PubMed Scopus (267) Google Scholar). Jung et al. found that PAF indeed interacts with both Bmi1 and EZH2, but not other PRC2 components, and EZH2 overexpression augments β-catenin transcriptional activity. PAF, EZH2, and β-catenin are found to co-occupy promoters of several Wnt/β-catenin target genes in CRC and mouse embryonic stem cells (ESCs); PAF depletion decreases EZH2 association with the c-Myc promoter, and β-catenin depletion decreases the association of both PAF and EZH2 with the promoter. Thus the β-catenin-PAF-EZH2 complex appears to constitute a chain of coactivators (Figure 1), and indeed PAF, which binds to both β-catenin and EZH2, enhances β-catenin-EZH2 coimmunoprecipitation. Together with an earlier study (Shi et al., 2007Shi B. Liang J. Yang X. Wang Y. Zhao Y. Wu H. Sun L. Zhang Y. Chen Y. Li R. et al.Mol. Cell. Biol. 2007; 27: 5105-5119Crossref PubMed Scopus (267) Google Scholar), these results suggest a model that PAF brings EZH2 and the associated RNA polymerase II mediator complex to β-catenin target genes for transactivation in CRCs (Figure 1). Consistent with this model, transgenic overexpression of PAF in the mouse intestine induces β-catenin-dependent target and reporter gene expression, intestinal overgrowth, and adenoma formation in vivo and crypt organoid expansion in vitro, resembling Wnt/β-catenin signaling activation in the gastrointestinal tract. PAF and EZH2 represent newer additions to β-catenin’s plethora of coactivators (Mosimann et al., 2009Mosimann C. Hausmann G. Basler K. Nat. Rev. Mol. Cell Biol. 2009; 10: 276-286Crossref PubMed Scopus (444) Google Scholar), which offer multiple routes to engage the basal transcription apparatus. These coactivators may have partially redundant and/or context-dependent functions for numerous Wnt/β-catenin-dependent gene expression programs. Mouse mutants that lack an individual β-catenin coactivator are often viable (MacDonald et al., 2009MacDonald B.T. Tamai K. He X. Dev. Cell. 2009; 17: 9-26Abstract Full Text Full Text PDF PubMed Scopus (4142) Google Scholar, Mosimann et al., 2009Mosimann C. Hausmann G. Basler K. Nat. Rev. Mol. Cell Biol. 2009; 10: 276-286Crossref PubMed Scopus (444) Google Scholar). Paf−/− mice are viable but exhibit defects in hematopoietic stem cell properties (Amrani et al., 2011Amrani Y.M. Gill J. Matevossian A. Alonzo E.S. Yang C. Shieh J.H. Moore M.A. Park C.Y. Sant’Angelo D.B. Denzin L.K. J. Exp. Med. 2011; 208: 1757-1765Crossref PubMed Scopus (22) Google Scholar). PAF is also expressed in self-renewing mouse ESCs, but the expression is downregulated upon ESC differentiation (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Whether PAF has a general role in self-renewal of ESCs and adult stem cells through its role in β-catenin signaling or DNA replication and repair pathways remains to be investigated. PAF-β-catenin interaction is observed under Wnt stimulation, likely as a consequence of β-catenin accumulation (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). In some cell types, PAF is ubiquitinated and degraded by the anaphase-promoting complex and thus exhibits the lowest level in the G1 phase of the cell cycle (Emanuele et al., 2011Emanuele M.J. Ciccia A. Elia A.E. Elledge S.J. Proc. Natl. Acad. Sci. USA. 2011; 108: 9845-9850Crossref PubMed Scopus (82) Google Scholar). In these cells PAF may have a limited role as a coactivator for β-catenin-dependent transcription, which primarily occurs in G1. But in CRC and other cancers where PAF is overexpressed, PAF may have a prominent role as a β-catenin coactivator. PAF-PCNA interaction is well documented (e.g., Yu et al., 2001Yu P. Huang B. Shen M. Lau C. Chan E. Michel J. Xiong Y. Payan D.G. Luo Y. Oncogene. 2001; 20: 484-489Crossref PubMed Scopus (88) Google Scholar). Intriguingly, in CRCs with high levels of β-catenin, PAF-PCNA interaction is barely detectable (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). Conversely, in cells where the basal level of Wnt/β-catenin signaling is low, PAF-PCNA interaction is detected but is diminished by Wnt3a or pharmacological agents that stabilize β-catenin (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). PAF seems to interact with β-catenin and PCNA via an overlapping domain (although this remains to be better defined), offering a possible explanation why PAF-β-catenin and PAF-PCNA complexes appear to be mutually exclusive (Jung et al., 2013Jung H.-Y. Jun S. Lee M. Kim H.-C. Wang X. Ji H. McCrea P.D. Park J.-I. Molecular Cell. 2013; 52 (this issue): 193-205Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar). This may simply reflect the fact that PAF-β-catenin (for RNA transcription) and PAF-PCNA (for DNA replication/repair) complexes act in G1 and S, respectively (Figure 1). However, when β-catenin levels are high in Wnt-stimulated cells or in CRCs, one may speculate that β-catenin accumulation could inhibit PAF-PCNA complex formation in the S phase, thereby enabling Wnt/β-catenin signaling to modulate PAF-PCNA-dependent DNA replication and repair/bypass pathways (Figure 1). This would constitute an unsuspected role for Wnt/β-catenin signaling in genomic stability beyond its established transcriptional function and could have implications for tumorigenesis. PAF and EZH2 Induce Wnt/β-Catenin Signaling HyperactivationJung et al.Molecular CellSeptember 19, 2013In BriefFine 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. Full-Text PDF Open Archive" @default.
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• W2024006296 title "PAF Makes It EZ(H2) for β-Catenin Transactivation" @default.
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