广州医科大学毛新良研究组发现，抑制Otub1/磷酸化STAT3轴可用于非小细胞肺癌的治疗。相关论文于2024年8月28日在线发表在《中国药理学报》杂志上。

通过筛选去泛素酶（Dub）文库，研究人员发现Otub1能增加STAT3的转录活性。作为一种去泛素酶，Otub1结合pSTAT3-Y705并特异性地去除其K48连接的泛素化，从而防止其降解并促进非小细胞肺癌（NSCLC）细胞存活。Otub1/pSTAT3-Y705轴可能是治疗NSCLC的潜在靶点。

为了探索这一概念，研究人员通过基于STAT3识别元件驱动的荧光素酶测定筛选了FDA批准的药物和天然产物文库，其中发现克唑替尼能阻止pSTAT3-Y705的去泛素化并促进其降解。与其已知的诱导ALK阳性NSCLC细胞凋亡的作用不同，克唑替尼抑制了ALK完整型NSCLC细胞增殖和克隆形成，但不引起凋亡。此外，克唑替尼还抑制了小鼠NSCLC异种移植瘤的生长。综合来看，这些发现将Otub1鉴定为第一个pSTAT3-Y705的去泛素酶，并表明Otub1/pSTAT3-Y705轴是治疗NSCLC的有前景的靶点。

据介绍，转录因子STAT3是NSCLC治疗的一个有前景的靶点。STAT3的活性主要依赖于酪氨酸705的磷酸化（pSTAT3-Y705），但对pSTAT3-Y705的调控尚不清楚。

附：英文原文

Title: Inhibiting the Otub1/phosphorylated STAT3 axis for the treatment of non-small cell lung cancer

Author: 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

Issue&Volume: 2024-08-28

Abstract: 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.

DOI: 10.1038/s41401-024-01366-w

Source: https://www.nature.com/articles/s41401-024-01366-w