Program for Cancer and Cell Biology, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences; Peking University International Cancer Institute; MOE Key Laboratory of Carcinogenesis and Translational Research and State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing 100191, China.
School of Life Sciences, MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing 100084, China.
Nucleic Acids Res. 2022 Apr 22;50(7):3817-3834. doi: 10.1093/nar/gkac189.
Reactive oxygen species (ROS) are constantly produced in cells, an excess of which causes oxidative stress. ROS has been linked to regulation of the Hippo pathway; however, the underlying detailed mechanisms remain unclear. Here, we report that MOB1, a substrate of MST1/2 and co-activator of LATS1/2 in the canonical Hippo pathway, interacts with and is acetylated at lysine 11 by acetyltransferase CBP and deacetylated by HDAC6. MOB1-K11 acetylation stabilizes itself by reducing its binding capacity with E3 ligase Praja2 and subsequent ubiquitination. MOB1-K11 acetylation increases its phosphorylation and activates LATS1. Importantly, upstream oxidative stress signals promote MOB1 acetylation by suppressing CBP degradation, independent of MST1/2 kinase activity and HDAC6 deacetylation effect, thereby linking oxidative stress to activation of the Hippo pathway. Functionally, the acetylation-deficient mutant MOB1-K11R promotes lung cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo, compared to the wild-type MOB1. Clinically, acetylated MOB1 corresponds to better prediction of overall survival in patients with non-small cell lung cancer. Therefore, as demonstrated, an oxidative stress-CBP regulatory axis controls MOB1-K11 acetylation and activates LATS1, thereby activating the Hippo pathway and suppressing YAP/TAZ nuclear translocation and tumor progression.
活性氧（ROS）在细胞中不断产生，过量的 ROS 会导致氧化应激。ROS 与 Hippo 通路的调节有关；然而，其潜在的详细机制尚不清楚。在这里，我们报告说，MOB1 是经典 Hippo 通路中 MST1/2 的底物和 LATS1/2 的共激活剂，与乙酰转移酶 CBP 相互作用并在赖氨酸 11 处被其乙酰化，并被 HDAC6 去乙酰化。MOB1-K11 乙酰化通过降低其与 E3 连接酶 Praja2 的结合能力及其随后的泛素化来稳定自身。MOB1-K11 乙酰化增加其磷酸化并激活 LATS1。重要的是，上游氧化应激信号通过抑制 CBP 降解来促进 MOB1 乙酰化，这独立于 MST1/2 激酶活性和 HDAC6 去乙酰化效应，从而将氧化应激与 Hippo 通路的激活联系起来。在功能上，与野生型 MOB1 相比，缺乏乙酰化的突变型 MOB1-K11R 促进了肺癌细胞在体外的增殖、迁移和侵袭，并加速了体内肿瘤的生长。临床上，乙酰化的 MOB1 与非小细胞肺癌患者的总生存率的更好预测相关。因此，如所证明的，氧化应激-CBP 调节轴控制 MOB1-K11 乙酰化并激活 LATS1，从而激活 Hippo 通路并抑制 YAP/TAZ 核易位和肿瘤进展。
