MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge, CB2 0QH, UK.
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre,, Robinson Way, Cambridge, CB2 0RE, UK.
Nat Commun. 2019 Feb 13;10(1):724. doi: 10.1038/s41467-018-08164-z.
Bcl9 and Pygo are Wnt enhanceosome components that effect β-catenin-dependent transcription. Whether they mediate β-catenin-dependent neoplasia is unclear. Here we assess their roles in intestinal tumourigenesis initiated by Apc loss-of-function (Apc), or by Apc encoding a partially-functional Apc truncation commonly found in colorectal carcinomas. Intestinal deletion of Bcl9 extends disease-free survival in both models, and essentially cures Apc mice of their neoplasia. Loss-of-Bcl9 synergises with loss-of-Pygo to shift gene expression within Apc-mutant adenomas from stem cell-like to differentiation along Notch-regulated secretory lineages. Bcl9 loss also promotes tumour retention in Apc mice, apparently via relocating nuclear β-catenin to the cell surface, but this undesirable effect is not seen in Apc mice whose Apc truncation retains partial function in regulating β-catenin. Our results demonstrate a key role of the Wnt enhanceosome in β-catenin-dependent intestinal tumourigenesis and reveal the potential of BCL9 as a therapeutic target during early stages of colorectal cancer.
Bcl9 和 Pygo 是 Wnt 增强子组件，可影响 β-连环蛋白依赖性转录。它们是否介导β-连环蛋白依赖性肿瘤发生尚不清楚。在这里，我们评估了它们在由 APC 功能丧失（Apc）或 APC 编码的常见于结直肠癌的部分功能 APC 截断引发的肠道肿瘤发生中的作用。Bcl9 在肠道中的缺失可延长两种模型中的无病生存期，并可使 APC 小鼠的肿瘤基本痊愈。Bcl9 的缺失与 Pygo 的缺失协同作用，可使 APC 突变腺瘤内的基因表达从干细胞样向 Notch 调节的分泌谱系分化转变。Bcl9 的缺失还可促进 APC 小鼠的肿瘤保留，显然是通过将核β-连环蛋白重新定位到细胞表面，但在 APC 小鼠中未见这种不良影响，因为其 APC 截断保留了部分调节β-连环蛋白的功能。我们的研究结果表明 Wnt 增强子在β-连环蛋白依赖性肠道肿瘤发生中具有关键作用，并揭示了 BCL9 在结直肠癌早期作为治疗靶点的潜力。
