Glucose-Induced β-Catenin Acetylation Enhances Wnt Signaling in Cancer
Glucose-Induced β-Catenin Acetylation Enhances Wnt Signaling in Cancer
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DOI：
10.1016/j.molcel.2012.11.022
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发表时间：
2013-02-07
期刊：
影响因子：
16
通讯作者：
Garcia-Jimenez, Custodia
中科院分区：
文献类型：
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作者：
Chocarro-Calvo, Ana;Manuel Garcia-Martinez, Jose;Garcia-Jimenez, Custodia
β-连环蛋白的核积累是公认的癌症预后不良的标志物，它驱动癌细胞增殖和衰老旁路，并调节肠促胰岛素，脂肪和葡萄糖代谢的关键调节因子。以血糖水平升高为特征的糖尿病与癌症风险增加相关，部分原因是胰岛素生长因子1信号传导增加，但血糖升高是否直接影响癌症相关信号转导途径尚不清楚。在这里，我们表明，高葡萄糖是必不可少的β-连环蛋白的核定位响应Wnt信号。葡萄糖依赖性β-连环蛋白核保留需要赖氨酸354，并通过改变p300和沉默调节蛋白之间的平衡来介导，从而触发β-连环蛋白乙酰化。因此，β-连环蛋白在细胞核中积累，并在葡萄糖和Wnt联合刺激下激活靶启动子，但单独使用任一种刺激都不行。我们的研究结果揭示了高葡萄糖通过癌症相关Wnt/β-连环蛋白途径增强信号传导的机制，并可能解释与肥胖和糖尿病相关的癌症频率增加。
Nuclear accumulation of beta-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of beta-catenin in response to Wnt signaling. Glucose-dependent beta-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger beta-catenin acetylation. Consequently beta-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/beta-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.