The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer
The deubiquitinase USP10 mediates crosstalk between the LKB1/AMPK axis and Wnt/β‐catenin signaling in cancer
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DOI：
10.1002/1873-3468.14763
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发表时间：
2023-10
期刊：
影响因子：
3.5
通讯作者：
Yinuo Wang;Jingwei Liu;Shaoqin Zheng;L. Cao;Yiwei Li;Ren Sheng
中科院分区：
文献类型：
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作者：
Yinuo Wang;Jingwei Liu;Shaoqin Zheng;L. Cao;Yiwei Li;Ren Sheng
肝激酶B1（LKB 1）/AMP活化蛋白激酶（AMPK）轴枢转地控制细胞代谢并抑制各种癌症的异常生长。Wnt/β-catenin是一个经常失调的信号通路，驱动肿瘤发生。在这里，我们发现了LKB 1/AMPK轴和Wnt/β-catenin信号之间的串扰机制。活化的AMPK磷酸化去泛素化酶USP 10以增强关键支架蛋白Axin 1的去泛素化和稳定化。这种磷酸化也加强了USP 10和β-catenin之间的结合，并支持β-catenin的相变。这两个过程同时抑制Wnt/β-catenin振幅，并以临床相关方式抑制结直肠癌生长。总的来说，我们建立了一个串扰途径，LKB 1/AMPK通过该途径调节癌症中的Wnt/β-catenin信号传导。USP 10在此过程中起着枢纽作用，从而使LKB 1/AMPK能够通过调节代谢和细胞增殖来抑制肿瘤生长。
The liver kinase B1 (LKB1)/AMP‐activated protein kinase (AMPK) axis pivotally controls cell metabolism and suppresses abnormal growth in various cancers. Wnt/β‐catenin is a frequently dysregulated signaling pathway that drives oncogenesis. Here, we discovered a crosstalk mechanism between the LKB1/AMPK axis and Wnt/β‐catenin signaling. Activated AMPK phosphorylates the deubiquitinase USP10 to potentiate the deubiquitination and stabilization of the key scaffold protein Axin1. This phosphorylation also strengthens the binding between USP10 and β‐catenin and supports the phase transition of β‐catenin. Both processes suppress Wnt/β‐catenin amplitude in parallel and inhibit colorectal cancer growth in a clinically relevant manner. Collectively, we established a crosstalk route by which LKB1/AMPK regulates Wnt/β‐catenin signaling in cancer. USP10 acts as the hub in this process, thus enabling LKB1/AMPK to suppress tumor growth via regulation of both metabolism and cell proliferation.