USP21-EGFR signaling axis is functionally implicated in metastatic colorectal cancer.

IF 6.1 2区 生物学 Q1 CELL BIOLOGY
Ji Hye Shin, Mi-Jeong Kim, Ji Young Kim, Bongkum Choi, Yeeun Kang, Seo Hyun Kim, Ha-Jeong Lee, Dohee Kwon, Yong Beom Cho, Kyeong Kyu Kim, Eunyoung Chun, Ki-Young Lee
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引用次数: 0

Abstract

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.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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