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Paradoxical activation of AMPK by glucose drives selective EP300 activity in colorectal cancer.
PLOS Biology ( IF 7.8 ) Pub Date : 2020-06-30 , DOI: 10.1371/journal.pbio.3000732
María Gutiérrez-Salmerón 1 , José Manuel García-Martínez 1 , Javier Martínez-Useros 2 , María Jesús Fernández-Aceñero 3 , Benoit Viollet 4 , Severine Olivier 4 , Jagat Chauhan 5 , Silvia R Lucena 1 , Antonio De la Vieja 6 , Colin R Goding 5 , Ana Chocarro-Calvo 1, 5 , Custodia García-Jiménez 1
Affiliation  

Coordination of gene expression with nutrient availability supports proliferation and homeostasis and is shaped by protein acetylation. Yet how physiological/pathological signals link acetylation to specific gene expression programs and whether such responses are cell-type–specific is unclear. AMP-activated protein kinase (AMPK) is a key energy sensor, activated by glucose limitation to resolve nutrient supply–demand imbalances, critical for diabetes and cancer. Unexpectedly, we show here that, in gastrointestinal cancer cells, glucose activates AMPK to selectively induce EP300, but not CREB-binding protein (CBP). Consequently, EP300 is redirected away from nuclear receptors that promote differentiation towards β-catenin, a driver of proliferation and colorectal tumorigenesis. Importantly, blocking glycogen synthesis permits reactive oxygen species (ROS) accumulation and AMPK activation in response to glucose in previously nonresponsive cells. Notably, glycogen content and activity of the ROS/AMPK/EP300/β-catenin axis are opposite in healthy versus tumor sections. Glycogen content reduction from healthy to tumor tissue may explain AMPK switching from tumor suppressor to activator during tumor evolution.



中文翻译:

葡萄糖对AMPK的反常激活会驱动结直肠癌的选择性EP300活性。

基因表达与养分利用率的协调支持增殖和体内平衡,并受蛋白质乙酰化的影响。然而,尚不清楚生理/病理信号如何将乙酰化与特定基因表达程序联系起来,以及此类反应是否为细胞类型特异性。AMP激活的蛋白激酶(AMPK)是一种关键的能量传感器,通过限制葡萄糖来激活,以解决对糖尿病和癌症至关重要的营养供应-需求不平衡。出乎意料的是,我们在这里显示出,在胃肠道癌细胞中,葡萄糖激活AMPK以选择性地诱导EP300,而不是CREB结合蛋白(CBP)。因此,EP300从促进分化的核受体重定向到β-catenin,β-catenin是增殖和结直肠肿瘤发生的驱动力。重要的,阻断糖原合成可以响应先前无反应的细胞中的葡萄糖而使活性氧(ROS)积累和AMPK活化。值得注意的是,在健康与肿瘤切片中,ROS / AMPK / EP300 /β-catenin轴的糖原含量和活性相反。从健康组织到肿瘤组织的糖原含量降低可能解释了AMPK在肿瘤进化过程中从抑癌剂转变为活化剂。

更新日期:2020-06-30
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