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The E3 ubiquitin ligase TRIM17 promotes gastric cancer survival and progression via controlling BAX stability and antagonizing apoptosis

Cell Death & Differentiation volume 30, pages 2322–2335 (2023)Cite this article

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Abstract

Tripartite motif 17 (TRIM17) belongs to a subfamily of the RING-type E3 ubiquitin ligases, and regulates several cellular processes and pathological conditions including cancer. However, its potential function in gastric cancer (GC) remains obscure. Here, we have found TRIM17 mRNA and protein levels are both upregulated in human GC compared with normal specimens, and TRIM17 upregulation indicates poor survival for GC patients. Functionally, TRIM17 was found to act as an oncogene by promoting the proliferation and survival of GC cell lines AGS and HGC-27. Mechanistically, TRIM17 acts to interact with BAX and promote its ubiquitination and proteasomal degradation, leading to a deficiency in BAX-dependent apoptosis in GC cells in the absence and presence of apoptosis stimuli. Moreover, TRIM17 and BAX expression levels are inversely correlated in human GC specimens. Our data thus suggest TRIM17 contributes to gastric cancer survival through regulating BAX protein stability and antagonizing apoptosis, which provides a promising therapeutic target for GC treatment and a biomarker for prognosis.

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Fig. 1: TRIM17 is upregulated in GC patients with poor clinical prognosis.
Fig. 2: TRIM17 deficiency suppresses the proliferation and induces apoptosis in GC cells.
Fig. 3: TRIM17 interacts with and regulates BAX stability.
Fig. 4: TRIM17 ubiquitinates BAX in vivo and in vitro, with its E3 liagase activity dependent on the RING or SPRY domain.
Fig. 5: BAX knockdown abrogates the TRIM17 depletion-induced tumor suppressing function in vitro.
Fig. 6: TRIM17 negatively regulates apoptotic responses induced by anticancer drugs and its depletion promotes chemosensitization.
Fig. 7: Expression levels of TRIM17 and BAX are inversely correlated in human GC specimens and cell lines.

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Data availability

The TGCA data in Fig. 1A and supplementary Fig. S1A-B were downloaded from http://xena.ucsc.edu/public/. The Kaplan-Meier survival analysis in Figs. 1B and 7C was downloaded from https://www.kmplot.com. The GSEA data in Fig. 3A and supplementary Fig. S3A were retrieved from http://www.gsea-msigdb.org/gsea/downloads.jsp. All of the original immunoblots were provided as Supplementary material. Other raw data that support the findings of this study can be made available upon reasonable request.

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Acknowledgements

This project is sponsored by the National Natural Science Foundation of China (Nos. 82002966; 82073241), the CAMS Innovation Fund for Medical Sciences (Nos. 2021-I2M-1-030; 2022-I2M-2-002; 2022-I2M-1-016) and the National Key Research and Development Program (2022YFC2804700).

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Author notes

  1. Hang Yang

    Present address: The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, China

  2. These authors contributed equally: Jiajia Shen, Hang Yang.

Authors and Affiliations

  1. Department of Biochemistry, Institute of Medicinal Biotecnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    Jiajia Shen, Hang Yang, Xinran Qiao, Yang Chen, Liyun Zheng, Jingyu Lin & Zhen Wang

  2. CAS_Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Jingyu Lang

  3. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Agency for Science, Technology, and Research (A*STAR), Biopolis, Singapore, Singapore

    Qiang Yu

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Contributions

ZW, JS, and HY designed the experiments; JS and HY performed most of the animal, functional, and biochemical experiments; HY performed bioinformatical analyses and tissue IHC staining; XQ, YC, LZ, and JL(in) performed some animal and biochemical experiments; JL(ang), QY and ZW assisted in the analysis of some experiments and interpreted the data; ZW, JS and HY drafted the manuscript; ZW conceived and supervised the project. All authors have reviewed and approved the submission.

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Correspondence to Zhen Wang.

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All animal experiments were approved by the Ethics Committee of the Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences in China, and conducted in accordance with the regulations and operational procedures of experimental animal management.

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Shen, J., Yang, H., Qiao, X. et al. The E3 ubiquitin ligase TRIM17 promotes gastric cancer survival and progression via controlling BAX stability and antagonizing apoptosis. Cell Death Differ 30, 2322–2335 (2023). https://doi.org/10.1038/s41418-023-01221-1

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