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

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.

TBX3 acts as tissue-specific component of the Wnt/β-catenin enhanceosome

“…We induced intestinal epithelium-specific recombination of Pygo1/2 loxP alleles (Pygo1/2-KO), that efficiently deleted these genes in the whole epithelium, including the stem cells compartment (Figure supplement 1A and 1B). Consistently with recent reports (Mieszczanek et al, 2019;Talla and Brembeck, 2016), and similarly to deletion of Bcl9/9l (Deka et al, 2010;Mani et al, 2009;Moor et al, 2015), Pygo1/2-KO displayed not overt phenotypic defects (Figure 1B and Figure supplement 1C). We were surprised in noticing that the expression of Lgr5, the most important intestinal stem cell marker and Wnt target gene (Barker et al, 2007), was heavily downregulated upon loss of Bcl9/9l but unaffected in Pygo1/2-KO ( Figure 1C).…”

“…This was surprising, since BCL9/9L proteins were thought to act as mere "bridge" proteins that tethered PYGO to the b-catenin transcriptional complex ( Figure 1A) (Fiedler et al, 2015;Mosimann et al, 2009). Both BCL9 and PYGO proteins have been implicated in colorectal carcinogenesis (Gay et al, 2019;Jiang et al, 2020;Mieszczanek et al, 2019;Talla and Brembeck, 2016). We tested if the consequence of the deletion of Bcl9/9l and Pygo1/2 genes was also different in the context of carcinogenesis.…”

“…Curiously however, BCL9 and PYGO always seem to act as a "duet" (Kennedy et al, 2010). Importantly, BCL9/9L and PYGO proteins were found to significantly contribute to the malignant traits typical of Wnt-induced CRCs (Deka et al, 2010;Gay et al, 2019;Jiang et al, 2020;Mani et al, 2009;Mieszczanek et al, 2019;Moor et al, 2015;Talla and Brembeck, 2016). These observations provided impetus to consider the BCL9/PYGO axis as relevant "targetable" unit in CRC (Lyou et al, 2017;Mieszczanek et al, 2019;Talla and Brembeck, 2016;Zimmerli et al, 2017).…”

Augmentation of Myc-Dependent Mitotic Gene Expression by the Pygopus2 Chromatin Effector

“…The Pygo2/MYC Interaction Is Distinct from Canonical Wnt Signaling Many mitogenic pathways converge to amplify MYC expression in cancer, including canonical Wnt signaling (Dang, 2012). Pygo2 is a component of the active Wnt/b-catenin complex, which also activates myc transcription (Chen et al, 2010;Gu et al, 2012;Liu et al, 2013;Talla and Brembeck, 2016;Zhou et al, 2016). It is possible that in our Pygo2-depletion experiments, loss of MYC-dependent cell division proteins was indirectly due to Figure S3.…”

Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein–protein interfaces of nuclear factors

“…Interestingly, Pygo2 plays crucial roles in mammary gland outgrowth as well as in mammary cancer stem cells. Furthermore, it may also play a role in some models of intestinal tumour initiation and progression (Talla and Brembeck, ). Additionally, there is evidence that Pygo's chromatin binding ability is required for mammary gland outgrowth (Watanabe et al, ).…”