College of Life and Health Science, Northeastern University, Shenyang, China.
College of Basic Medical Science, China Medical University, Shenyang, China.
FEBS Lett. 2023 Dec;597(24):3061-3071. doi: 10.1002/1873-3468.14763. Epub 2023 Nov 2.
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.
肝激酶 B1（LKB1）/腺苷酸活化蛋白激酶（AMPK）轴是细胞代谢的关键调节因子，可抑制多种癌症中的异常生长。Wnt/β-连环蛋白信号通路是一种经常失调的信号通路，可驱动肿瘤发生。在这里，我们发现了 LKB1/AMPK 轴和 Wnt/β-连环蛋白信号之间的串扰机制。活化的 AMPK 磷酸化去泛素化酶 USP10，增强关键支架蛋白 Axin1 的去泛素化和稳定。这种磷酸化还增强了 USP10 和 β-连环蛋白之间的结合，并支持 β-连环蛋白的相变。这两个过程平行抑制 Wnt/β-连环蛋白的幅度，并以临床相关的方式抑制结直肠癌细胞的生长。总的来说，我们建立了一条 LKB1/AMPK 调节癌症中 Wnt/β-连环蛋白信号的串扰途径。USP10 在此过程中充当枢纽，从而使 LKB1/AMPK 能够通过调节代谢和细胞增殖来抑制肿瘤生长。
