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Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase

1
Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon 16419, Korea
2
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea
3
Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06531, Korea
4
Samsung Medical Center, Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul 06531, Korea
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(1), 207; https://doi.org/10.3390/cancers12010207
Received: 18 December 2019 / Revised: 2 January 2020 / Accepted: 4 January 2020 / Published: 14 January 2020
(This article belongs to the Special Issue Targeting the Ubiquitin Pathway in Cancer)
Fos-related-antigen-1 (Fra-1), a member of the activator protein-1 (AP-1) transcription factor superfamily, has an essential role in cancer progress and metastasis and Fra-1 is considered a therapeutic target in metastatic cancer including metastatic colorectal cancer (mCRC). However, its regulation at protein level has not yet been clearly elucidated. We found that ubiquitin-specific protease 21 (USP21) increases Fra-1 stability by deubiquitinating Fra-1 and enhances the expression of Fra-1 target genes in colon cancer cells. We also showed that USP21 controlled Fra-1-dependent migration and invasion activities. The oncogenic property of USP21 was confirmed by a significant reduction in liver metastasis when USP21-knockdown cancer cells were injected intrasplenically into mice. Consistently, clinicopathological analysis of colorectal cancer patients revealed a correlation of USP21 expression with high-grade carcinoma and life span. These results demonstrate that USP21 enhances Fra-1 stability and AP-1 target gene expression by deubiquitinating Fra-1. Therefore, USP21 is considered an attractive therapeutic target in mCRC with high Fra-1 expression. View Full-Text
Keywords: deubiquitination; USP21; Fra-1; colorectal cancer; metastasis deubiquitination; USP21; Fra-1; colorectal cancer; metastasis
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Yun, S.-I.; Hong, H.K.; Yeo, S.-Y.; Kim, S.-H.; Cho, Y.B.; Kim, K.K. Ubiquitin-Specific Protease 21 Promotes Colorectal Cancer Metastasis by Acting as a Fra-1 Deubiquitinase. Cancers 2020, 12, 207.

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