PUBLICATION

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

Authors
Walker, M.P., Stopford, C.M., Cederlund, M., Fang, F., Jahn, C., Rabinowitz, A.D., Goldfarb, D., Graham, D.M., Yan, F., Deal, A.M., Fedoriw, Y., Richards, K.L., Davis, I.J., Weidinger, G., Damania, B., Major, M.B.
ID
ZDB-PUB-150205-7
Date
2015
Source
Science signaling   8(362): ra12 (Journal)
Registered Authors
Cederlund, Maria, Fang, Fang, Jahn, Christopher, Weidinger, Gilbert
Keywords
none
MeSH Terms
  • 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*
PubMed
25650440 Full text @ 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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping