Journal
SCIENCE SIGNALING
Volume 8, Issue 362, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005654
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Funding
- National Cancer Institute (NCI) Center Core Support Grant [P30CA016086]
- state of North Carolina (University Cancer Research Fund)
- NIH (New Innovator Award) [1-DP2-OD007149-01]
- NIH [T32-CA009156-35]
- American Cancer Society [MSRG-12-086-01-TBG]
- [R01CA163217]
- [P01CA019014]
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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 beta-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 beta-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 beta-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of beta-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking beta-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with beta-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.
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