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STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression

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Abstract

Dual-specificity mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1/CL-100) has been documented to promote breast cancer cell survival and chemoresistance. MKP-1 is an unstable protein that is ubiquitinated and degraded via the ubiquitin-proteasome system. However, it is not clear how MKP-1 protein stability is regulated in breast cancer. In this study, we performed a genome-wide siRNA library screen of deubiquitinases (DUBs) and identified STAMBPL1 as an MKP-1 DUB in breast cancer cells. STAMBPL1 interacts with MKP-1 and stabilizes MKP-1 via deubiquitination. Both STAMBPL1 and MKP-1 depletion sensitize breast cancer cells to cisplatin in vitro and in vivo, and ectopic overexpression of MKP-1 partially rescues STAMBPL1 depletion-induced cisplatin sensitivity. Furthermore, STAMBPL1 and MKP-1 depletion increased breast cancer sensitivity to cisplatin by increasing the phosphorylation and activation of c-Jun N-terminal protein kinase (JNK). Collectively, our findings not only identify STAMBPL1 as an MKP-1 DUB but also reveal a critical mechanism that regulates MKP-1 expression in breast cancer. Our findings indicate that the STAMBPL1/MKP-1 axis represents a potential therapeutic target in breast cancer.

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Fig. 1: STAMBPL1 is a candidate DUB that stabilizes MKP-1 expression.
Fig. 2: STAMBPL1 stabilizes MKP-1 protein through deubiquitination.
Fig. 3: STAMBPL1 interacts with MKP-1.
Fig. 4: STAMBPL1 depletion sensitizes breast cancer cells to cisplatin treatment.
Fig. 5: STAMBPL1 overexpression inhibits breast cancer cell sensitivity to cisplatin.
Fig. 6: STAMBPL1 promotes breast cancer cell resistance to cisplatin treatment via MKP-1/JNK signaling.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China [2020YFA0112300 and 2018YFC2000400 to CC], National Natural Science Foundation of China [81772847, 82073270 and U1502222 to RL; 81572610 to JH; 81830087 and U2102203 to CC], a Shortage of Talent of Project in Guangdong Province, China [4YF16002G], Project of Innovative Research Team of Yunnan Province [2019HC005] and Yunnan Fundamental Research Projects (202001AW070018 and 202101AS070050).

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Author notes

  1. These authors contributed equally: Rong Liu, Guangxi Yang, Min Bao.

Authors and Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Rong Liu, Guangxi Yang, Min Bao, Zhongmei Zhou, Wenjing Liu, Xiaoyan Jiang & Ceshi Chen

  2. Translational Cancer Research Center, Peking University First Hospital, 100034, Beijing, China

    Rong Liu

  3. Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215000, China

    Min Bao

  4. Department of Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, 110000, China

    Xiaoyun Mao

  5. Department of Pathology, The Center of Pathological Diagnosis and Research, Affiliated Hospital, Guangdong Medical University, Zhanjiang, 524000, China

    Di Zhu, Xinle Ren & Jian Huang

  6. KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China

    Ceshi Chen

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Contributions

RL and CC designed the experiments. RL, GY, and MB carried out the experiments and analyzed the data. XJ and WL helped to perform the animal experiments. ZZ, XM, DZ, and XR provided technical support. RL wrote the manuscript, JH, RL, and CC revised the manuscript.

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Correspondence to Rong Liu, Jian Huang or Ceshi Chen.

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Liu, R., Yang, G., Bao, M. et al. STAMBPL1 promotes breast cancer cell resistance to cisplatin partially by stabilizing MKP-1 expression. Oncogene 41, 2265–2274 (2022). https://doi.org/10.1038/s41388-022-02252-7

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