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

Yun, Sun-Il; Hong, Hye Kyung; Yeo, So-Young; Kim, Seok-Hyung; Cho, Yong Beom; Kim, Kyeong Kyu

doi:10.3390/cancers12010207

Cited by 38 publications

(34 citation statements)

References 45 publications

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“…In this study, USP21, another member of the USP subfamily of DUBs, was reported to be highly expressed in GC tissue and cells. The expression trend is consistent with that in breast cancer ( Arceci et al, 2019 ) and colorectal cancer ( Yun et al, 2020 ). Previous research found that the nuclear localization of USP21 in pancreas cancer is positively correlated with advanced tumor grades and expression levels, and overexpression of USP21 promotes cell stemness ( Hou et al, 2019 ).…”

Section: Discussionsupporting

confidence: 84%

“…USP21 is proven to deubiquitinate TCF7 ( Hou et al, 2019 ), YY1 ( Xu et al, 2020 ), FOXM1 ( Arceci et al, 2019 ), EZH2 ( Chen et al, 2017 ), RIG-1 ( Fan et al, 2014 ), Fra-1 ( Yun et al, 2020 ), IL-8 ( Peng et al, 2016 ), and other genes to stabilize their expression. This study testified that USP21 in GC cells could bind to GATA3 to regulate its expression.…”

Section: Discussionmentioning

confidence: 99%

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De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer

Guo

Shi

Lin

et al. 2021

Front. Cell Dev. Biol.

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USP21 is a kind of deubiquitinating enzymes involved in the malignant progression of various cancers, while its role in gastric cancer (GC) and the specific molecular mechanism are still unclear. This study probed into the function of USP21 in vitro and in vivo, and discussed the regulatory mechanism of USP21 in GC in vitro. We reported that USP21 promoted GC cell proliferation, migration, invasion, and stemness in vitro, and regulated GC tumor growth and cell stemness in mice in vivo. USP21 stabilized the expression of GATA3 by binding to GATA3. Besides, GATA3 also regulated the expression of MAPK1 at the transcriptional level. A series of in vitro experiments testified that USP21 regulated the expression of MAPK1 by binding to transcription factor GATA3, thereby regulating the tumor growth and cell stemness of GC. Overall, this study identified a new USP21/GATA3/MAPK1 axis, which plays a pivotal role in promoting the malignant progression of GC and might provide a potential target for treatment.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer

Guo

Shi

Lin

et al. 2021

Front. Cell Dev. Biol.

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“…USP21 ampli cation was also observed in other cancer types (Fig. 4a), which is consistent with previous studies that USP21 regulates cell proliferation and metastasis in colorectal cancer and pancreas cancer (Yun et al 2020;Hou et al 2019). Next, we con rmed the expression levels of PD-L1 and USP21 in LUSC and found that upregulated expression of PD-L1 accounted for 80% (395 of 494) of LUSC samples, while USP21 accounted for 76% (375 of 494) of LUSC samples (Fig.…”

Section: Usp21 Functions As a Pd-l1 Dubsupporting

confidence: 90%

Deubiquitination and Stabilization of PD-L1 by USP21

Yang

Yan

et al. 2021

Preprint

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Background: The immunotherapy for different types of cancers that targeting programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) has highlighted the importance of suppressing specific T cell responses. Recently, several studies have shown that the expression level of PD-L1 in tumor cells is positively correlated with tumor metastasis as well as recurrence rate. The potent effects of post-translational modifications (PTMs) for PD-L1, such as ubiquitination, glycosylation, phosphorylation and palmitoylation, have been reported to be related to immunosuppression. However, the regulation of PD-L1 degradation in cancers is still not well understood. In this paper, we mainly investigate the deubiquitination regulation of PD-L1. Methods: The protein levels of PD-L1 and USP21 were detected by Immunoblotting and immunohistochemistry. The interaction between PD-L1 and USP21 was determined by co-immunoprecipitation. The deubiquitination of PD-L1 was determined by in vitro deubiquitination assay. The deubiquitination sites of PD-L1 were identified by mass spectrometry analysis. The expression of mRNA in target tissues was presented by bioinformatics analysis.Results: Overexpression of USP21 significantly increased PD-L1 abundance and knockdown of USP21 induced degradation of PD-L1. In vitro deubiquitination assay showed that USP21-WT reduced polyubiquitin chains from PD-L1 while USP21-C221A did not. Furthermore, five lysines in intracellular segment of PD-L1 are potential deubiquitin sites and cancer-derived mutations of PD-L1 in Asp276 have the ability to enhance the deubiquitination of PD-L1 mediated by USP21. Finally, we found that USP21 is the frequently amplified deubiquitinase in lung cancer, especially in lung squamous cell carcinoma, and its amplification co-occurs with the upregulation of PD-L1 levels. Moreover, IHC analysis showed stronger staining of PD-L1 and USP21 in lung cancer samples than adjacent tissues. Conclusion: We identified USP21 as a novel deubiquitinase of PD-L1. Hopefully, targeting PD-L1 by inhibiting USP21 might be a potentially novel strategy for the treatment of lung cancer.

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“…Fra-1 is not able to transform the cells on its own. However, a high expression of Fra1 promotes cell proliferation and survival, as well as angiogenesis of human cancers (32)(33)(34). Furthermore, overexpression of Fra1 confers chemo/radioresistance in multiple human cancer models (35,36).…”

Section: Discussionmentioning

confidence: 99%

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

Gao¹,

Li²,

Zhou

et al. 2020

Oncol Rep

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High expression of cyclin D1 has a crucial role in the maintenance of unlimited cell growth in human cancer cells. The present study indicated that cyclin D1 was overexpressed in human non-small cell lung cancer (NSCLC) tumor tissues and cell lines. Knockout of cyclin D1 suppressed NSCLC cell growth, colony formation and in vivo tumor growth. Of note, the natural product xanthohumol (Xanth) inhibited NSCLC cells via the downregulation of cyclin D1. A further mechanistic study revealed that Xanth suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1 (Fra1), which eventually inhibited the transcriptional activity of activator protein-1 and decreased the mRNA level of cyclin D1. Furthermore, suppression of ERK1/2 impaired Fra1 phosphorylation and enhanced Xanth-induced Fra1 ubiquitination and degradation. In addition, the S265D mutation compromised Xanth-induced Fra1 degradation. Finally, the in vivo anti-tumor effect of Xanth was validated in a xenograft mouse model. In summary, the present results indicated that targeting ERK1/2-Fra1-cyclin D1 signaling is a promising anti-tumor strategy for NSCLC treatment.

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

Cited by 38 publications

References 45 publications

De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer

De-Ubiquitinating Enzymes USP21 Regulate MAPK1 Expression by Binding to Transcription Factor GATA3 to Regulate Tumor Growth and Cell Stemness of Gastric Cancer

Deubiquitination and Stabilization of PD-L1 by USP21

Xanthohumol targets the ERK1/2‑Fra1 signaling axis to reduce cyclin D1 expression and inhibit non‑small cell lung cancer

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