RRC ID 40004
Author Walker MP, Stopford CM, Cederlund M, Fang F, Jahn C, Rabinowitz AD, Goldfarb D, Graham DM, Yan F, Deal AM, Fedoriw Y, Richards KL, Davis IJ, Weidinger G, Damania B, Major MB.
Title FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma.
Journal Sci Signal
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.
Volume 8(362)
Pages ra12
Published 2015-2-3
DOI 10.1126/scisignal.2005654
PII 8/362/ra12
PMID 25650440
PMC PMC4356208
MeSH Animals Enhancer Elements, Genetic Forkhead Transcription Factors / metabolism* Gene Expression Profiling Gene Expression Regulation, Neoplastic* HEK293 Cells Humans Ligands Lymphoma, Large B-Cell, Diffuse / metabolism* Mass Spectrometry Mice Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Prognosis Protein Isoforms / metabolism Repressor Proteins / metabolism* Transcription Factor 7-Like 2 Protein / metabolism Wnt Proteins / metabolism* Wnt Signaling Pathway* Zebrafish beta Catenin / metabolism*
IF 6.467
Times Cited 32
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)/isi04