Dataset Information

FOXP1 potentiates Wnt/?-catenin signaling in diffuse large B cell lymphoma.

ABSTRACT: The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry-coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates ?-catenin-dependent, Wnt-dependent gene expression. Gain- and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved enhancer of Wnt signaling. In a Wnt-dependent fashion, FOXP1 formed a complex with ?-catenin, TCF7L2 (transcription factor 7-like 2), and the acetyltransferase CBP [CREB (adenosine 3',5'-monophosphate response element-binding protein)-binding protein], and this complex bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of ?-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of ?-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking ?-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with ?-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.

SUBMITTER: Walker MP

PROVIDER: S-EPMC4356208 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma.

Walker Matthew P MP Stopford Charles M CM Cederlund Maria M Fang Fang F Jahn Christopher C Rabinowitz Alex D AD Goldfarb Dennis D Graham David M DM Yan Feng F Deal Allison M AM Fedoriw Yuri Y Richards Kristy L KL Davis Ian J IJ Weidinger Gilbert G Damania Blossom B Major Michael B MB

Science signaling 20150203 362

The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry-coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates β-catenin-dependent, Wnt- ...[more]

PMID: 25650440

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Project description:Glycoprotein prostaglandin D2 synthase (PTGDS) is a member of the lipocalin superfamily and plays dual roles in prostaglandins metabolism and lipid transport. PTGDS has been involved in various cellular processes including the tumorigenesis of solid tumors, yet its role in carcinogenesis is contradictory and the significance of PTGDS in hematological malignancies is ill-defined. Here, we aimed to explore the expression and function of PTGDS in diffuse large B-cell lymphoma (DLBCL), especially the potential role of PTGDS inhibitor, AT56, in lymphoma therapy. Remarkable high expression of PTGDS was found in DLBCL, which was significantly correlated with poor prognosis. PTGDS overexpression and rhPTGDS were found to promote cell proliferation. Besides, in vitro and in vivo studies indicated that PTGDS knockdown and AT56 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and invasion, and enhanced the drug sensitivity to adriamycin and bendamustine through promoting DNA damage. Moreover, the co-immunoprecipitation-based mass spectrum identified the interaction between PTGDS and MYH9, which was found to promote DLBCL progression. PTGDS inhibition led to reduced expression of MYH9, and then declined activation of the Wnt-β-catenin-STAT3 pathway through influencing the ubiquitination and degradation of GSK3-β in DLBCL. The rescue experiment demonstrated that PTGDS exerted an oncogenic role through regulating MYH9 and then the Wnt-β-catenin-STAT3 pathway. Based on point mutation of glycosylation sites, we confirmed the N-glycosylation of PTGDS in Asn51 and Asn78 and found that abnormal glycosylation of PTGDS resulted in its nuclear translocation, prolonged half-life, and enhanced cell proliferation. Collectively, our findings identified for the first time that glycoprotein PTGDS promoted tumorigenesis of DLBCL through MYH9-mediated regulation of Wnt-β-catenin-STAT3 signaling, and highlighted the potential role of AT56 as a novel therapeutic strategy for DLBCL treatment.

Dataset Information

FOXP1 potentiates Wnt/?-catenin signaling in diffuse large B cell lymphoma.

Publications

FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma.

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