Tuning WNT-β-catenin signaling via BCL9 proteins for targeting colorectal cancer cells.
Tuning WNT-β-catenin signaling via BCL9 proteins for targeting colorectal cancer cells.
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DOI：
10.1016/j.ebiom.2015.11.033
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发表时间：
2015-12
期刊：
影响因子：
11.1
通讯作者：
Beaulieu JF
中科院分区：
文献类型：
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作者：
Beaulieu JF
经典的WNT信号通路最终参与游离β-连环蛋白的细胞质水平的调节。当失活时，未掺入粘附连接中的β-连环蛋白被基于腺瘤性结肠息肉病（APC）的蛋白质复合物捕获，磷酸化，然后被蛋白酶体加工降解。通过WNT配体（例如在位于下隐窝中的肠干细胞龛中发现的那些）的激活防止β-连环蛋白泛素化，从而允许其在细胞质中积累并穿梭至细胞核，在细胞核中其与淋巴增强子结合因子/T细胞因子（TCF）家族的DNA结合蛋白缔合以反式激活特异性基因表达，例如MYC，CCLD 1和其他驱动细胞增殖和干性的基因（Niehrs 2012）。结直肠癌（CRC）细胞经常显示组成型活性WNT-β-连环蛋白信号通路，这是APC或编码基于APC的蛋白破坏复合物或β-连环蛋白本身的其他基因突变的结果，这使得β-连环蛋白在细胞核中积累并有助于细胞转化（Barker和Clevers 2006; Krausova和Korinek 2014）。在正常细胞和转化细胞中，有许多因子相互作用并调节WNT级联反应。如开创性综述（Cruciat and Niehrs 2013; de Lau et al. 2014）所述，WNT信号传导在配体-受体水平受到一系列调节信号强度的抑制剂和激活剂的严格控制。此外，WNT信号传导还在转录水平上受到一系列β-连环蛋白相互作用辅因子的调节，如环AMP反应元件结合蛋白和B细胞淋巴瘤9（BCL 9和BCL 9 L），这些辅因子可增强活性（Holland et al. 2013）。虽然WNT通路的许多这些调节剂代表了癌症治疗的潜在靶标，但它们的破坏也可能导致健康组织的WNT信号传导通路的改变，这是在临床前研究和最终临床研究的设计中必须考虑的困难（Barker和Clevers 2006）。在这种情况下，值得注意的是，与β-连环蛋白辅因子BCL 9/9 L相关的细胞应答的影响可能是环境依赖性的。事实上，在小鼠中，肠上皮中Bcl 9/9 l的消融消除了与化学诱导的结肠直肠肿瘤中的上皮-间质转化（EMT）和干性相关的基因的表达，这表明与肿瘤相关的性状在结肠直肠癌中的表达是不稳定的。
The canonical WNT signaling pathway is ultimately involved in the regulation of cytoplasmic levels of free β-catenin. When inactive, the β-catenin not incorporated in adherent junctions is captured by the adenomatous polyposis coli (APC)-based protein complex, phosphorylated and then processed for degradation by the proteasome. Activation by WNT ligands such as those found in the intestinal stem cell niche located in the lower crypts prevents β-catenin ubiquitination allowing its accumulation in the cytoplasm and shuttling to the nucleus where it associates with the DNA-binding proteins of the lymphoid enhancer-binding factor/T-cell factor (TCF) family to transactivate specific gene expression such as MYC, CCLD1 and other genes that drive cell proliferation and stemness (Niehrs 2012). Colorectal cancer (CRC) cells frequently display a constitutively active WNT–β-catenin signaling pathway as a consequence of mutations in APC or other genes that encode the APC-based protein destruction complex or β-catenin itself, which allows β-catenin to accumulate in the nucleus and contribute to cellular transformation (Barker and Clevers 2006; Krausova and Korinek 2014). There are many factors that interact and modulate the WNT cascade in both normal and transformed cells. As depicted in seminal reviews (Cruciat and Niehrs 2013; de Lau et al. 2014), WNT signaling is strictly controlled at the ligand–receptor level by a series of inhibitors and activators that regulate signal strength. Furthermore, WNT signaling is also modulated at the transcriptional level by a series of β-catenin-interacting co-factors such as cyclic AMP response element-binding protein and B-cell lymphoma 9 (BCL9 and BCL9L) which can strengthen the activity (Holland et al. 2013). While many of these modulators of the WNT pathway represent potential targets for cancer therapeutics, their disruption can also lead to alterations in the WNT signaling pathway of healthy tissues, a difficulty that has to be taken into consideration in the design of pre-clinical and, eventually, clinical studies (Barker and Clevers 2006). In this context, it is interesting to note that the impact of the cellular response associated with the β-catenin co-factor BCL9/9L may be context-dependent. Indeed, in the mouse, ablation of Bcl9/9l in the intestinal epithelium abrogates the expression of genes related to epithelial–mesenchymal transformation (EMT) and stemness in chemically induced colorectal tumors suggesting that the traits associated