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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: Otub1 promotes STAT3 transcriptional activity.
Fig. 2: Otub1 stabilizes phosphorylated STAT3 at Y705 but not other forms.
Fig. 3: Otub1 binds to pY705 and increases its K48-linked polyubiquitination.
Fig. 4: Otub1 promotes NSCLC cell survival and its expression level is associated with poor outcomes of NSCLC patients.
Fig. 5: Crizotinib inhibits STAT3 phosphorylation at Y705 in NSCLC cells by promoting its turnover in proteasomes via K48-linked polyubiquitination.
Fig. 6: Crizotinib inhibits NSCLC cell proliferation by arresting cells at G2 phase.
Fig. 7: Inhibition of the Otub1/pSTAT3 axis by crizotinib impairs the growth of NSCLC xenografts in immunodeficient mice.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thanked Prof. Zheng Hui from Soochow University, China, for his generous gift of the Dub library. The authors also thanked Prof. Michael F. Moran from University of Toronto, Canada, for his kind discussion and text editing of the text.

Funding

This work was partly supported by Special Projects in Key Areas for Guangdong Provincial Colleges and Universities (#2021ZDZX2009 to XLM), the National Natural Science Foundation of China (#32100577 to YR), the Guangzhou Municipal Science and Technology Project (#202002030059 to XLM), and by Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (#JCXKJS2022A05 to XLM).

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  1. These authors contributed equally: Zi-yang Liu, Ya-wen Zhang, Hai-xia Zhuang

Authors and Affiliations

  1. 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

    Zi-yang Liu, Hai-xia Zhuang, Yu-jie Ou, Qiu-yun Jiang, Ping-fei Li, Yuan-ming He & Xin-liang Mao

  2. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Ya-wen Zhang & Ying Ren

  3. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, China

    Ying Ren

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Contributions

XLM designed the study; ZYL, YWZ, HXZ, YJO, QYJ, PFL, and YMH conducted experiments. XLM, ZYL, and YWZ analyzed data; XLM, ZYL, and YR wrote the manuscript.

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Correspondence to Xin-liang Mao.

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Liu, Zy., Zhang, Yw., Zhuang, Hx. et al. Inhibiting the Otub1/phosphorylated STAT3 axis for the treatment of non-small cell lung cancer. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01366-w

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