Bcl9/Bcl9l Are Critical for Wnt-Mediated Regulation of Stem Cell Traits in Colon Epithelium and Adenocarcinomas

Abstract

Canonical Wnt signaling plays a critical role in stem cell maintenance in epithelial homeostasis and carcinogenesis. Here, we show that in the mouse this role is critically mediated by Bcl9/Bcl9l, the mammalian homologues of Legless, which in Drosophila is required for Armadillo/β-catenin signaling. Conditional ablation of Bcl9/Bcl9l in the intestinal epithelium, where the essential role of Wnt signaling in epithelial homeostasis and stem cell maintenance is well documented, resulted in decreased expression of intestinal stem cell markers and impaired regeneration of ulcerated colon epithelium. Adenocarcinomas with aberrant Wnt signaling arose with similar incidence in wild-type and mutant mice. However, transcriptional profiles were vastly different: Whereas wild-type tumors displayed characteristics of epithelial-mesenchymal transition (EMT) and stem cell-like properties, these properties were largely abrogated in mutant tumors. These findings reveal an essential role for Bcl9/ Bcl9l in regulating a subset of Wnt target genes involved in controlling EMT and stem cell-related features and suggest that targeting the Bcl9/Bcl9l arm of Wnt signaling in Wnt-activated cancers might attenuate these traits, which are associated with tumor invasion, metastasis, and resistance to therapy.

Epigenetic regulation of aging stem cells

“…In addition, the roles for transcriptional cofactors of b-catenin, BCL9/BCL9L and PYGO2, in adult stem cell proliferation have been associated with their function as readers of histone marks H3K4me2 and H3K4me3 (Fiedler et al, 2008;Chen et al, 2010). BCL9 and homolog BCL9L are necessary for adult stem cellmediated regeneration of muscle and colon epithelium (Brack et al, 2009;Deka et al, 2010), whereas PYGO2 promotes self-renewal of mammary progenitor cells through regulation of cell cycle progression (Gu et al, 2009;Chen et al, 2010). In mammary progenitors, PYGO2 binds to H3K4me2 and H3K4me3 and recruits histone methyltransferases to catalyze this active mark at WNT target genes (Gu et al, 2009;Chen et al, 2010).…”

Structure-Based Design of 1,4-Dibenzoylpiperazines as β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction Inhibitors

“…BCL9 and its paralogue B9L connect β-catenin with the chromatin remodeler Pygopus (Pygo). 19,20 BCL9 and B9L were observed highly overexpressed in Wnt-dependent cancer cells (but not in normal tissues). 19,21,23,24 The individual knockdown of BCL9 and B9L 19,21−25 or the use of dominant negative BCL9 or B9L 21,23 inhibited the activity of canonical Wnt signaling in cell-based reporter assays, downregulated transcription of Wnt target genes, inhibited cancer cell migration, and induced an epithelial-like phenotype in colon cancer and multiple myeloma cells.…”

“…25 The conditional ablation of BCL9 and B9L in mice reduced Wnt responsive genes that promote cancer stem cells and epithelial-to-mesenchymal transition. 19,20,26 BCL9/B9L-ablation in murine oncogenic intestinal organoids provoked differentiation and abrogated tumorigenicity. 26 However, the conditional gene ablation of BCL9 and B9L showed normal cell lineage commitment and proliferation, 19,20 indicating the selective disruption of the β-catenin/BCL9 PPI might not affect normal tissue homeostasis.…”

“…19,20,26 BCL9/B9L-ablation in murine oncogenic intestinal organoids provoked differentiation and abrogated tumorigenicity. 26 However, the conditional gene ablation of BCL9 and B9L showed normal cell lineage commitment and proliferation, 19,20 indicating the selective disruption of the β-catenin/BCL9 PPI might not affect normal tissue homeostasis. Two other merits that make the β-catenin/BCL9 PPI appealing for inhibitor design are (1) the binding site of β-catenin for BCL9 partially overlaps with that for cadherin but has no overlap with that for Axin and APC; and (2) the interaction between β-catenin and BCL9 or B9L is relatively weak with a dissociation constant (K d ) of 0.465 μM.…”

The Tumor-Suppressor WWOX and HDAC3 Inhibit the Transcriptional Activity of the β-Catenin Coactivator BCL9-2 in Breast Cancer Cells

“…BCL9-2 would also stimulates b-catenin nuclear import (10,11). BCL9-2 is overexpressed in breast and colon cancers and this overexpression would promote colon adenocarcinoma by enhancing the neoplastic transforming activity of the Wnt/b-catenin pathway (13,14).…”