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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

E3 Ligase TRIM21 Deficiency-Driven GAS2L3 Accumulation Facilitates Oncogenic Progression in Breast Cancer

  • Peiying Li1
  • Chunyan Zhao1
  • Yuanyuan Ren1
  • Yuannan Wei2
  • Nan Zhang1
  • Lingbiao Xin1
  • Yanan Sun1
  • Jie Yang1
  • Jinyan He1
  • Xin Liu1
  • Xingjie Gao1
  1. 1Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China
  2. 2Department of Immunology, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
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Abstract

GAS2L3, a member of the growth arrest-specific 2 protein family, is abnormally upregulated in multiple human cancers, implying its potential oncogenic role. However, the mechanisms underlying its stabilization and accumulation during breast cancer progression remain unclear. This study aimed to clarify the regulatory mechanism and oncogenic role of GAS2L3 in breast cancer. We analyzed the expression and prognostic value of GAS2L3 and its related signaling pathways using public breast cancer databases, and conducted functional assays to assess the malignant phenotypes of breast cancer cells. Mass spectrometry and co-immunoprecipitation were performed to identify and verify TRIM21 as a binding partner of GAS2L3. Ubiquitination and cycloheximide chase assays confirmed that TRIM21 facilitates the ubiquitination and proteasomal degradation of GAS2L3, while immunohistochemical staining of clinical specimens and mouse tissues verified their negative correlation. Rescue experiments further validated this regulatory axis. High GAS2L3 expression predicted poor prognosis and promoted breast cancer cell proliferation, migration, and invasion. Loss of TRIM21-mediated GAS2L3 degradation results in aberrant GAS2L3 accumulation, and the TRIM21–GAS2L3 axis drives breast cancer malignant progression, providing potential prognostic biomarkers and therapeutic targets for breast cancer.

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Cite

BibTeXRIS
BibTeX
@article{li2026ligase,
  title = {{E3 Ligase TRIM21 Deficiency-Driven GAS2L3 Accumulation Facilitates Oncogenic Progression in Breast Cancer}},
  author = {Peiying Li and Chunyan Zhao and Yuanyuan Ren and Yuannan Wei and Nan Zhang and Lingbiao Xin and Yanan Sun and Jie Yang and Jinyan He and Xin Liu and Xingjie Gao},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = nov,
  doi = {10.3390/ijms27219937},
  url = {https://www.mdpi.com/1422-0067/27/21/9937},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - E3 Ligase TRIM21 Deficiency-Driven GAS2L3 Accumulation Facilitates Oncogenic Progression in Breast Cancer
AU  - Peiying Li
AU  - Chunyan Zhao
AU  - Yuanyuan Ren
AU  - Yuannan Wei
AU  - Nan Zhang
AU  - Lingbiao Xin
AU  - Yanan Sun
AU  - Jie Yang
AU  - Jinyan He
AU  - Xin Liu
AU  - Xingjie Gao
PY  - 2026
DA  - 2026/11/06
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219937
UR  - https://www.mdpi.com/1422-0067/27/21/9937
AB  - GAS2L3, a member of the growth arrest-specific 2 protein family, is abnormally upregulated in multiple human cancers, implying its potential oncogenic role. However, the mechanisms underlying its stabilization and accumulation during breast cancer progression remain unclear. This study aimed to clarify the regulatory mechanism and oncogenic role of GAS2L3 in breast cancer. We analyzed the expression and prognostic value of GAS2L3 and its related signaling pathways using public breast cancer databases, and conducted functional assays to assess the malignant phenotypes of breast cancer cells. Mass spectrometry and co-immunoprecipitation were performed to identify and verify TRIM21 as a binding partner of GAS2L3. Ubiquitination and cycloheximide chase assays confirmed that TRIM21 facilitates the ubiquitination and proteasomal degradation of GAS2L3, while immunohistochemical staining of clinical specimens and mouse tissues verified their negative correlation. Rescue experiments further validated this regulatory axis. High GAS2L3 expression predicted poor prognosis and promoted breast cancer cell proliferation, migration, and invasion. Loss of TRIM21-mediated GAS2L3 degradation results in aberrant GAS2L3 accumulation, and the TRIM21–GAS2L3 axis drives breast cancer malignant progression, providing potential prognostic biomarkers and therapeutic targets for breast cancer.
SN  - 1422-0067
ER  -