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TRIM17-mediated ubiquitination and degradation of RBM38 promotes cisplatin resistance in non-small cell lung cancer

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Abstract

Cisplatin (CDDP)-based chemotherapy is commonly used to treat advanced non-small cell lung cancer (NSCLC). However, the efficacy is limited by the development of drug resistance. Tripartite motif (TRIM) proteins typically have E3 ubiquitin ligase activities and modulate protein stability. In the present study, we screened for chemosensitivity-regulating TRIM proteins using CDDP-resistant NSCLC cell lines. We show that TRIM17 is upregulated in CDDP-resistant NSCLC cells and tumors compared to CDDP-sensitive counterparts. NSCLC patients with high TRIM17 expression in tumors have shorter progression-free survival than those with low TRIM17 expression after CDDP chemotherapy. Knockdown of TRIM17 increases the sensitivity of NSCLC cells to CDDP both in vitro and in vivo. In contrast, overexpression of TRIM17 promotes CDDP resistance in NSCLC cells. TRIM17-mediated CDDP resistance is associated with attenuation of reactive oxygen species (ROS) production and DNA damage. Mechanistically, TRIM17 interacts with RBM38 and promotes K48-linked ubiquitination and degradation of RBM38. TRIM17-induced CDDP resistance is remarkably reversed by RBM38. Additionally, RBM38 enhances CDDP-induced production of ROS. In conclusion, TRIM17 upregulation drives CDDP resistance in NSCLC largely by promoting RBM38 ubiquitination and degradation. Targeting TRIM17 may represent a promising strategy for improving CDDP-based chemotherapy in NSCLC.

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Data availability

All data that support the findings of this study are available from the corresponding author (lihongmin@med.uestc.edu.cn) upon reasonable request.

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Funding

This work was supported by the Research Foundation from Sichuan Provincial Health and Family Planning Commission of China (17PJ039).

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Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Tian Zhong, Jing Zhang & Xingren Liu

  2. Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China

    Tian Zhong, Jing Zhang, Xingren Liu & Hongmin Li

  3. Cancer Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China

    Hongmin Li

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  1. Tian Zhong
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This study was conceived, designed, and interpreted by TZ, JZ and HML. TZ, JZ and XGL undertook the experiments. TZ drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xingren Liu or Hongmin Li.

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This study was approved by the Institutional Review Board of University of Electronic Science and Technology of China (Chengdu, China). Written informed consent for research was obtained from each patient. The protocols involving animals were approved by the Institutional Animal Care and User Committee of University of Electronic Science and Technology of China.

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Tian Zhong and Jing Zhang contributed equally to this work and should be considered co-first authors.

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Zhong, T., Zhang, J., Liu, X. et al. TRIM17-mediated ubiquitination and degradation of RBM38 promotes cisplatin resistance in non-small cell lung cancer. Cell Oncol. 46, 1493–1507 (2023). https://doi.org/10.1007/s13402-023-00825-6

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