2. Academic Validation
  3. TRIM21/USP15 balances ACSL4 stability and the imatinib resistance of gastrointestinal stromal tumors

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

  • Br J Cancer. 2024 Jan 5. doi: 10.1038/s41416-023-02562-x.
Zhiwei Cui # 1 2,  Haoyu Sun # 1 2,  Zhishuang Gao # 3,  Chao Li # 4,  Tingting Xiao # 5,  Yibo Bian 6,  Zonghang Liu 1 2,  Tianhao Gu 1 2,  Jianan Zhang 1 2,  Tengyun Li 1 2,  Qianzheng Zhou 1 2,  Zhongyuan He 1 2,  Bowen Li 1 2,  Fengyuan Li 1 2,  Zekuan Xu 1 2,  Hao Xu 7 8
Affiliations

Affiliations

  • 1 Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 2 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China.
  • 3 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 4 Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China.
  • 5 Department of Cardiology, the Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, 213003, Jiangsu, China.
  • 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.
  • 7 Department of General Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. hxu@njmu.edu.cn.
  • 8 Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medical University, Nanjing, 211166, China. hxu@njmu.edu.cn.
  • # Contributed equally.
PMID: 38182686 DOI: 10.1038/s41416-023-02562-x
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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