Shin Ji Hye, Kim Mi-Jeong, Kim Ji Young, Choi Bongkum, Kang Yeeun, Kim Seo Hyun, Lee Ha-Jeong, Kwon Dohee, Cho Yong Beom, Kim Kyeong Kyu, Chun Eunyoung, Lee Ki-Young
Department of Immunology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Department of Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
Cell Death Discov. 2024 Dec 18;10(1):492. doi: 10.1038/s41420-024-02255-1.
The emerging role of ubiquitin-specific peptidase 21 (USP21) in stabilizing Fra-1 (FOSL1) highlights its involvement in promoting colorectal cancer (CRC) metastasis. Additionally, a reciprocal link between EGFR signaling and Fra-1 activation has been identified, mediated through matrix metalloproteinases (MMPs). However, the functional implications of the USP21-EGFR signaling axis in metastatic CRC (mCRC) are not fully understood. To investigate the clinical correlation between USP21 and EGFR expression, RNA-Seq data from tumor tissues (n = 27) and matched normal tissues (n = 27) of 27 mCRC patients were analyzed. Functional studies were performed, including the use of CRISPR/Cas9 to generate USP21-knockout (USP21-KO) CRC cells, in vitro assays for cancer progression and tumor formation, in vivo xenograft assays in NSG mice. Additionally, the therapeutic effect of the USP21 inhibitor, BAY-805, was evaluated. We found that elevated levels of USP21 and EGFR expression in mCRC patients were associated with poorer survival outcomes. Mechanistically, USP21 was found to enhance EGFR stability by deubiquitinating EGFR, leading to reduced EGFR degradation. USP21-KO colon cancer cells exhibited significantly reduced proliferation, migration, colony formation, and 3D tumor spheroid formation in response to EGF. Furthermore, the tumorigenic activity in vivo was markedly diminished in NSG mice xenografted with USP21-KO colon cancer cells. Importantly, BAY-805 demonstrated a notable inhibitory effect on the formation of 3D tumor spheroids in colorectal cancer cells stimulated with EGF. These findings suggest that USP21 could be a valuable therapeutic target and predictive biomarker for managing mCRC driven by EGF.
泛素特异性蛋白酶21（USP21）在稳定Fra-1（FOSL1）中的新作用突出了其在促进结直肠癌（CRC）转移中的作用。此外，已确定表皮生长因子受体（EGFR）信号传导与Fra-1激活之间存在通过基质金属蛋白酶（MMP）介导的相互联系。然而，USP21-EGFR信号轴在转移性结直肠癌（mCRC）中的功能意义尚未完全了解。为了研究USP21与EGFR表达之间的临床相关性，分析了27例mCRC患者肿瘤组织（n = 27）和匹配的正常组织（n = 27）的RNA测序数据。进行了功能研究，包括使用CRISPR/Cas9生成USP21基因敲除（USP21-KO）的CRC细胞、癌症进展和肿瘤形成的体外试验、NSG小鼠体内异种移植试验。此外，还评估了USP21抑制剂BAY-805的治疗效果。我们发现mCRC患者中USP21和EGFR表达水平升高与较差的生存结果相关。从机制上讲，发现USP21通过去泛素化EGFR来增强其稳定性，从而减少EGFR降解。USP21-KO结肠癌细胞对表皮生长因子（EGF）的反应显示增殖、迁移、集落形成和3D肿瘤球体形成显著减少。此外，用USP21-KO结肠癌细胞异种移植的NSG小鼠体内的致瘤活性明显降低。重要的是，BAY-805对EGF刺激的结肠癌细胞中3D肿瘤球体的形成显示出显著的抑制作用。这些发现表明，USP21可能是治疗由EGF驱动的mCRC的有价值的治疗靶点和预测生物标志物。
