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

Br J Cancer. 2024 Mar;130(4):526-541. doi: 10.1038/s41416-023-02562-x. Epub 2024 Jan 5.


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.

MeSH terms

  • Animals
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics
  • Gastrointestinal Neoplasms* / drug therapy
  • Gastrointestinal Neoplasms* / genetics
  • Gastrointestinal Neoplasms* / metabolism
  • Gastrointestinal Stromal Tumors* / drug therapy
  • Gastrointestinal Stromal Tumors* / genetics
  • Gastrointestinal Stromal Tumors* / pathology
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imatinib Mesylate / therapeutic use
  • Mice
  • Proto-Oncogene Proteins c-kit / metabolism
  • RNA, Small Interfering / pharmacology
  • Ubiquitin-Specific Proteases / pharmacology


  • Imatinib Mesylate
  • Antineoplastic Agents
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-kit
  • USP15 protein, human
  • Ubiquitin-Specific Proteases