USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer
Ji Hye Shin1, Mi-Jeong Kim1, Ji Young Kim1
1Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Cell Death Discovery
|December 18, 2024
Summary
Ubiquitin-specific peptidase 21 (USP21) promotes colorectal cancer (CRC) metastasis by stabilizing EGFR. Inhibiting USP21 with BAY-805 reduced tumor growth, suggesting USP21 as a therapeutic target for metastatic CRC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Ubiquitin-specific peptidase 21 (USP21) stabilizes Fra-1 (FOSL1), promoting colorectal cancer (CRC) metastasis.
- A link exists between EGFR signaling and Fra-1 activation via matrix metalloproteinases (MMPs).
- The role of the USP21-EGFR axis in metastatic CRC (mCRC) requires further elucidation.
Purpose of the Study:
- To investigate the clinical correlation between USP21 and EGFR expression in mCRC patients.
- To elucidate the functional role of the USP21-EGFR signaling axis in CRC progression and metastasis.
- To evaluate the therapeutic potential of USP21 inhibition in mCRC.
Main Methods:
- RNA-sequencing analysis of tumor and normal tissues from 27 mCRC patients.
- CRISPR/Cas9-mediated generation of USP21-knockout (USP21-KO) CRC cells.
- In vitro and in vivo assays, including proliferation, migration, colony formation, 3D tumor spheroid formation, and xenograft models in NSG mice.
- Evaluation of the USP21 inhibitor BAY-805.
Main Results:
- Elevated USP21 and EGFR expression correlated with poorer survival in mCRC patients.
- USP21 enhances EGFR stability by deubiquitination, reducing EGFR degradation.
- USP21-KO CRC cells showed significantly reduced proliferation, migration, colony formation, and spheroid formation.
- USP21-KO cells exhibited diminished tumorigenic activity in vivo.
- BAY-805 inhibited EGF-stimulated 3D tumor spheroid formation in CRC cells.
Conclusions:
- USP21 plays a critical role in promoting mCRC progression and metastasis by stabilizing EGFR.
- USP21 inhibition represents a promising therapeutic strategy for mCRC.
- USP21 may serve as a valuable predictive biomarker for EGF-driven mCRC.
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