转录因子 STAT3 是治疗非小细胞肺癌 (NSCLC) 的一个有前景的靶点。 STAT3 活性主要依赖于酪氨酸 705 (pSTAT3-Y705) 的磷酸化，但对 pSTAT3-Y705 的调节是难以捉摸的。通过筛选去泛素酶 (Dub) 文库，我们发现 Otub1 会增加 STAT3 转录活性。作为 Dub，Otub1 与 pSTAT3-Y705 结合，并特异性消除其 K48 连接的泛素化，从而防止其降解并促进 NSCLC 细胞存活。 Otub1/pSTAT3-Y705 轴可能成为 NSCLC 治疗的潜在靶点。为了探索这个概念，我们基于 STAT3 识别元件驱动的荧光素酶测定筛选 FDA 批准的药物和天然产物库，从中发现克唑替尼可以阻断 pSTAT3-Y705 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，但不抑制凋亡。此外，克唑替尼还抑制小鼠非小细胞肺癌异种移植物的生长。总而言之，这些发现确定 Otub1 是 pSTAT3-Y705 的第一个去泛素化酶，并表明 Otub1/pSTAT3-Y705 轴是治疗 NSCLC 的一个有希望的靶标。© 2024。作者，获得上海研究院独家许可中国科学院药物研究所、中国药理学会.

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.© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.