FOXP1 potentiates Wnt/?-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 ?-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 ?-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 ?-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of ?-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking ?-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with ?-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL.

SUBMITTER: Walker MP 

PROVIDER: S-EPMC4356208 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature