Ubiquitin‐specific protease 7 as a potential therapeutic target in dogs with hematopoietic malignancies

Background: Ubiquitin specific protease 48 (USP48) is a member of the deubiquitinating enzymes (DUBs) family. However, the function of USP48 in ovarian cancer remains unclear. Objective: The present study reveals that USP48 knockdown could significantly inhibit cell migration and invasion in ES2, 3AO and A2780 cells, without affecting cell proliferation. Methods: After carboplatin (CBP) treatment, the USP48 ablation increases the apoptosis rate, and the cleaved PARP and cleaved caspase 3 expression levels in ES2, 3AO and A2780 cells. The subcutaneous tumor and intraperitoneally injected experiments demonstrated that the USP48 knockdown significantly increases responsiveness to CBP, and alleviates the metastasis in vivo. Meanwhile, USP48 deficiency results in the improved survival of mice. Results: Finally, the analysis of clinical samples and the TCGA and Kaplan-Meier Plot database revealed that the high expression of USP48 in ovarian cancer patients is associated with poor survival and resistance to CBP therapy. Conclusion: In summary, USP48 may be a potential therapeutic target for ovarian cancer patients.

Download Full-text

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

Cancers ◽

10.3390/cancers12010207 ◽

2020 ◽

Vol 12 (1) ◽

pp. 207 ◽

Cited By ~ 1

Author(s):

Sun-Il Yun ◽

Hye Kyung Hong ◽

So-Young Yeo ◽

Seok-Hyung Kim ◽

Yong Beom Cho ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Cancer Metastasis ◽

Target Genes ◽

Metastatic Cancer ◽

Migration And Invasion ◽

Activator Protein 1 ◽

Specific Protease ◽

Ubiquitin Specific Protease

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.

Download Full-text

USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2

Cancers ◽

10.3390/cancers12051137 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1137 ◽

Cited By ~ 1

Author(s):

Jinhong Cho ◽

Jinyoung Park ◽

Sang Chul Shin ◽

Mihue Jang ◽

Jae-Hong Kim ◽

...

Keyword(s):

Ribosomal Protein ◽

Xenograft Model ◽

Deubiquitinating Enzymes ◽

Potential Therapeutic Target ◽

Mouse Xenograft Model ◽

Specific Protease ◽

Important Regulator ◽

Ubiquitin Specific Protease ◽

Cellular Stresses ◽

Ribosomal Stress

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) functions as an important regulator of p53. We show that ubiquitinated ribosomal protein S2 (RPS2) by Mouse double minute 2 homolog (MDM2) is deubiquitinated by USP47. USP47 inhibits the interaction between RPS2 and MDM2 thereby alleviating RPS2-mediated suppression of MDM2 under normal conditions. However, dissociation of USP47 leads to RPS2 binding to MDM2, which is required for the suppression of MDM2, consequently inducing up-regulation of the p53 level under ribosomal stress. Finally, we show that depletion of USP47 induces p53 and therefore inhibits cell proliferation, colony formation, and tumor progression in cancer cell lines and a mouse xenograft model. These findings suggest that USP47 could be a potential therapeutic target for cancer.

Download Full-text