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Cellular and Molecular

TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors

British Journal of Cancer volume 130, pages 526–541 (2024)Cite this article

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Abstract

Background

Imatinib has become an exceptionally effective targeted drug for treating gastrointestinal stromal tumors (GISTs). Despite its efficacy, the resistance to imatinib is common in GIST patients, posing a significant challenge to the effective treatment.

Methods

The expression profiling of TRIM21, USP15, and ACSL4 in GIST patients was evaluated using Western blot and immunohistochemistry. To silence gene expression, shRNA was utilized. Biological function of TRIM21, USP15, and ACSL4 was examined through various methods, including resistance index calculation, colony formation, shRNA interference, and xenograft mouse model. The molecular mechanism of TRIM21 and USP15 in GIST was determined by conducting Western blot, co-immunoprecipitation, and quantitative real-time PCR (qPCR) analyses.

Results

Here we demonstrated that downregulation of ACSL4 is associated with imatinib (IM) resistance in GIST. Moreover, clinical data showed that higher levels of ACSL4 expression are positively correlated with favorable clinical outcomes. Mechanistic investigations further indicated that the reduced expression of ACSL4 in GIST is attributed to excessive protein degradation mediated by the E3 ligase TRIM21 and the deubiquitinase USP15.

Conclusion

These findings demonstrate that the TRIM21 and USP15 control ACSL4 stability to maintain the IM sensitive/resistant status of GIST.

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Fig. 1: ACSL4 is aberrantly downregulated in GIST.
Fig. 2: ACSL4 mitigates imatinib resistance of GIST by promoting ferroptosis in vivo and in vitro.
Fig. 3: The E3 ligase TRIM21 interacts with and ubiquitinates ACSL4 to promote its degradation.
Fig. 4: TRIM21 promotes IM-resistance by inhibiting ferroptosis in vitro and in vivo.
Fig. 5: USP15 interacts with and deubiquitinates ACSL4.
Fig. 6: USP15 prevents IM-resistance via ferroptosis in vitro and in vivo.
Fig. 7: Correlation between TRIM21, USP15 and ACSL4 expression and association with GIST patient progression-free survival.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Author notes

  1. These authors contributed equally: Zhiwei Cui, Haoyu Sun, Zhishuang Gao, Chao Li, Tingting Xiao.

Authors and Affiliations

  1. Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China

    Zhiwei Cui, Haoyu Sun, Zonghang Liu, Tianhao Gu, Jianan Zhang, Tengyun Li, Qianzheng Zhou, Zhongyuan He, Bowen Li, Fengyuan Li, Zekuan Xu & Hao Xu

  2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China

    Zhiwei Cui, Haoyu Sun, Zonghang Liu, Tianhao Gu, Jianan Zhang, Tengyun Li, Qianzheng Zhou, Zhongyuan He, Bowen Li, Fengyuan Li, Zekuan Xu & Hao Xu

  3. Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Zhishuang Gao

  4. Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China

    Chao Li

  5. Department of Cardiology, the Affiliated Changzhou Second People’s Hospital of Nanjing Medical University, Changzhou, 213003, Jiangsu, China

    Tingting Xiao

  6. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Rd, Xi’an, 710032, Shaanxi, China

    Yibo Bian

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Contributions

Conception and design: ZWC; data acquisition, analysis, and interpretation: ZWC, HYS, TTX, HX, BWL, FYL; investigation: ZWC, ZSG, CL, TTX, YBB, JNZ, TYL, QZZ, ZYH; acquisition of patient specimens: ZSG, CL, ZHL, THG, ZKX and HX; article drafting and revising: ZWC, HYS, ZSG, CL and TTX; and article writing: ZWC. All authors approved the final version of the manuscript.

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Correspondence to Hao Xu.

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The collection of specimens and animal handling for the study have been reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University.

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Cui, Z., Sun, H., Gao, Z. et al. TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors. Br J Cancer 130, 526–541 (2024). https://doi.org/10.1038/s41416-023-02562-x

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