The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression.

Suranand B Talla,Felix H Brembeck

doi:10.18632/oncotarget.13016

Abstract

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.

Highlights

The members of the PYGOPUS and BCL9 protein families have been discovered as novel co-factors of canonical Wnt/ß-catenin signaling [1,2,3]
Analysis of mutant mice revealed that loss of Pygo2 neither disturbed normal embryonic development of the intestine nor impaired intestinal homeostasis or lineage commitment in adults (Schelp and Brembeck, unpublished data)
We have analyzed the in vivo role of Pygo2 using chemically induced colon cancer and conditional adenomatous polyposis coli gene (Apc) LOF and Ctnnb1 gain of function (GOF) mouse models

Summary

Introduction

The members of the PYGOPUS and BCL9 protein families have been discovered as novel co-factors of canonical Wnt/ß-catenin signaling [1,2,3]. Deregulation of the Wnt/ßcatenin signaling pathway was shown to be the primary driver of colon cancer development: the vast majority of sporadic human colon cancers harbor loss-of-function (LOF) mutations of the adenomatous polyposis coli gene (Apc) and less frequently gain of function (GOF) mutations of the ß-catenin encoding proto-oncogene Ctnnb1 [11]. These mutations constitutively activate Wnt/ ß-catenin signaling by preventing ß-catenin degradation, which results in accumulation and nuclear translocation of stabilized ß-catenin. SS-catenin interacts with TCF/LEF transcription factors to activate target gene transcription [12, 13]

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Conclusion