Liu Zi-Yang, Zhang Ya-Wen, Zhuang Hai-Xia, Ou Yu-Jie, Jiang Qiu-Yun, Li Ping-Fei, He Yuan-Ming, Ren Ying, Mao Xin-Liang
The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital of Guangzhou Medical University & Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
Acta Pharmacol Sin. 2025 Jan;46(1):184-195. doi: 10.1038/s41401-024-01366-w. Epub 2024 Aug 28.
The transcription factor STAT3 is a promising target for the treatment of non-small cell lung cancer (NSCLC). STAT3 activity is mainly dependent on phosphorylation at tyrosine 705 (pSTAT3-Y705), but the modulation on pSTAT3-Y705 is elusive. By screening a library of deubiquitinases (Dubs), we found that the Otub1 increases STAT3 transcriptional activity. As a Dub, Otub1 binds to pSTAT3-Y705 and specifically abolishes its K48-linked ubiquitination, therefore preventing its degradation and promoting NSCLC cell survival. The Otub1/pSTAT3-Y705 axis could be a potential target for the treatment of NSCLC. To explore this concept, we screen libraries of FDA-approved drugs and natural products based on STAT3-recognition element-driven luciferase assay, from which crizotinib is found to block pSTAT3-Y705 deubiquitination and promotes its degradation. Different from its known action to induce ALK positive NSCLC cell apoptosis, crizotinib suppresses ALK-intact NSCLC cell proliferation and colony formation but not apoptosis. Furthermore, crizotinib also suppresses NSCLC xenograft growth in mice. Taken together, these findings identify Otub1 as the first deubiquitinase of pSTAT3-Y705 and provide that the Otub1/pSTAT3-Y705 axis is a promising target for the treatment of NSCLC.
转录因子信号转导与转录激活因子3（STAT3）是治疗非小细胞肺癌（NSCLC）的一个有前景的靶点。STAT3的活性主要依赖于酪氨酸705位点的磷酸化（pSTAT3-Y705），但对pSTAT3-Y705的调控机制尚不清楚。通过筛选去泛素化酶（Dubs）文库，我们发现卵巢肿瘤相关蛋白1（Otub1）可增强STAT3的转录活性。作为一种去泛素化酶，Otub1与pSTAT3-Y705结合，并特异性消除其K48连接的泛素化，从而阻止其降解并促进NSCLC细胞存活。Otub1/pSTAT3-Y705轴可能是治疗NSCLC的潜在靶点。为了探究这一概念，我们基于STAT3识别元件驱动的荧光素酶检测筛选了FDA批准的药物和天然产物文库，从中发现克唑替尼可阻断pSTAT3-Y705的去泛素化并促进其降解。与已知的诱导ALK阳性NSCLC细胞凋亡的作用不同，克唑替尼抑制ALK完整的NSCLC细胞增殖和集落形成，但不诱导凋亡。此外，克唑替尼还可抑制小鼠体内NSCLC异种移植瘤的生长。综上所述，这些发现确定Otub1是pSTAT3-Y705的首个去泛素化酶，并表明Otub1/pSTAT3-Y705轴是治疗NSCLC的一个有前景的靶点。
