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
-
- Humans
- HEK293 Cells
- beta Catenin/metabolism*
- Wnt Signaling Pathway*
- Mice
- Forkhead Transcription Factors/metabolism*
- Prognosis
- Mass Spectrometry
- Protein Isoforms/metabolism
- Mice, Inbred NOD
- Neoplasm Transplantation
- Animals
- Mice, SCID
- Ligands
- Repressor Proteins/metabolism*
- Gene Expression Profiling
- Wnt Proteins/metabolism*
- Enhancer Elements, Genetic
- Zebrafish
- Transcription Factor 7-Like 2 Protein/metabolism
- Lymphoma, Large B-Cell, Diffuse/metabolism*
- Gene Expression Regulation, Neoplastic*
- PubMed
- 25650440 Full text @ Sci. Signal.
Citation
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. (2015) FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma. Science signaling. 8(362):ra12.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping