The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression.
Pygo2 acts as a co-activator of Wnt signaling in a nuclear complex with ß-catenin/BCL9/BCL9-2 to increase target gene transcription. Previous studies showed that Pygo2 is upregulated in murine intestinal tumors and human colon cancer, but is apparently dispensable for normal intestinal homeostasis. Here, we have evaluated the in vivo role of Pygo2 during intestinal tumorigenesis using Pygo2 deficient mice. We analyzed chemically induced colon tumor development and conditional intestine specific mouse models harboring either Apc loss-of-function (LOF) or Ctnnb1 gain-of-function (ß-catenin GOF). Remarkably, the number and size of chemically induced tumors was significantly reduced in Pygo2 deficient mice, suggesting that Pygo2 has a tumor promoting function. Furthermore, loss of Pygo2 rescued early tumorigenesis of Ctnnb1 GOF mutants. In contrast, Pygo2 ablation was not sufficient to prevent tumor development of Apc LOF mice. The effect on tumor formation by Pygo2 knockout was linked to the repression of specific deregulated Wnt target genes, in particular of c-Myc. Moreover, the role of Pygo2 appears to be associated with the signaling output of deregulated Wnt signaling in the different tumor models. Thus, targeting Pygo2 might provide a novel strategy to suppress tumor formation in a context dependent manner.
Tumor Biology and Signal Transduction, Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
Suranand B
SB
Talla
Tumor Biology and Signal Transduction, Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
Felix H
FH
Brembeck
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495267:CTNNB1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051176:beta Catenin; C495570:pygopus 2 protein, mouse; D001397:Azoxymethane
Pygo2; Wnt/ß-catenin signaling; adenomatous polyposis coli; colon cancer; ß-catenin