title: FOXP1 potentiates Wnt/β-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 β-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 β-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 β-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking β-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with β-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.
authors: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Matthew P
authors: MP
authors: Walker
authors: Division of Microbiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27516-7361, USA.
authors: Charles M
authors: CM
authors: Stopford
authors: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Maria
authors: M
authors: Cederlund
authors: Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Fang
authors: F
authors: Fang
authors: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Christopher
authors: C
authors: Jahn
authors: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Alex D
authors: AD
authors: Rabinowitz
authors: Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3175, USA.
authors: Dennis
authors: D
authors: Goldfarb
authors: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: David M
authors: DM
authors: Graham
authors: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Feng
authors: F
authors: Yan
authors: UNC Lineberger Comprehensive Cancer Center Biostatistics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Allison M
authors: AM
authors: Deal
authors: Department of Pathology and Laboratory, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Yuri
authors: Y
authors: Fedoriw
authors: Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27516-7361, USA.
authors: Kristy L
authors: KL
authors: Richards
authors: Carolina Center for Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
authors: Ian J
authors: IJ
authors: Davis
authors: Institute for Biochemistry and Molecular Biology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors: Gilbert
authors: G
authors: Weidinger
authors: Division of Microbiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27516-7361, USA.
authors: Blossom
authors: B
authors: Damania
authors: Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA. Division of Microbiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27516-7361, USA. benmajor@med.unc.edu.
authors: Michael B
authors: MB
authors: Major
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011379:Prognosis; D020033:Protein Isoforms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D008024:Ligands; D020033:Protein Isoforms; D012097:Repressor Proteins; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin
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