Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells

Xing, Zhiyuan; Sun, Fengbo; Wang, He; Wang, Zhiwei; Song, Xiuqi; Zhang, Fengjuan

doi:10.3892/ol.2018.8061

Cited by 11 publications

(9 citation statements)

References 24 publications

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“…Thus, this deubiquitinase may not act as an actual deubiquitinase. Several studies reported that USP39 may act as an oncogenic factor in several cancers, such as breast cancer, thyroid carcinoma, and hepatocellular carcinoma (24)(25)(26)(27), and they revealed a novel role for USP39-mediated mRNA splicing in the process of cell proliferation (28). However, it is less clear whether or how USP39 plays a role in other biological functions, such as antiviral immunity.…”

Section: Discussionmentioning

confidence: 99%

USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN–Induced Antiviral Immunity

Yihong

Guo

Sun

et al. 2020

The Journal of Immunology

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Deubiquitinating enzymes (DUBs) are cysteine proteases that reverse the ubiquitination by removing ubiquitins from the target protein. The human genome encodes ∼100 potential DUBs, which can be classified into six families, influencing multiple cellular processes, such as antiviral responses, inflammatory responses, apoptosis, etc. To systematically explore the role of DUBs involved in antiviral immunity, we performed an RNA interference-based screening that contains 97 human DUBs. We identified that ubiquitin-specific protease (USP) 39 expression modulates the antiviral activity, which is, to our knowledge, a previously unknown function of this enzyme. Small interfering RNA knockdown of USP39 significantly enhanced viral replication, whereas overexpression of USP39 had an opposite effect. Mechanistically, USP39 does not affect the production of type I IFN but significantly promotes JAK/STAT downstream of type I signaling by enhancing IFN-stimulated response elements promoter activity and expression of IFN-stimulated genes. Interestingly, USP39, previously considered not to have the deubiquitinase activity, in this study is proved to interact with STAT1 and sustain its protein level by deubiqutination. Furthermore, we found that through novel mechanism USP39 can significantly decrease K6-linked but not K48-linked ubiquitination of STAT1 for degradation. Taken together, these findings uncover that USP39 is, to our knowledge, a new deubiquitinase that positively regulates IFN-induced antiviral efficacy.

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Section: Discussionmentioning

confidence: 99%

USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN–Induced Antiviral Immunity

Yihong

Guo

Sun

et al. 2020

The Journal of Immunology

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“…USP39 is also reported to be a pivotal regulator of EGFR pre-mRNA splicing [10]. In addition, an oncogenic role for USP39 has been reported in many malignant tumors, such as prostate cancer [10], oral squamous cell carcinoma [11], gastric cancer [12], melanoma [13], osteosarcoma [14], breast cancer [15], hepatocellular carcinoma [16], medullary thyroid carcinoma [17], lung cancer [18], pancreatic cancer [19], colorectal cancer [20], and renal cell carcinoma [21]. However, the role of USP39 in glioma has not been well defined.…”

Section: Introductionmentioning

confidence: 99%

RNA splicing factor USP39 promotes glioma progression by inducing TAZ mRNA maturation

Ding

Zhang

et al. 2019

Oncogene

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Increasing evidence demonstrates that ubiquitin specific protease 39 (USP39) plays an oncogenic role in various human tumors. Here, using expression analysis of the publicly available Oncomine database, clinical glioma patient samples, and glioma cells, we found that USP39 was overexpressed in human gliomas. Knockdown of USP39 in glioma cells demonstrated that the protein promoted cell growth, invasion and migration in vitro and in a tumor model in nude mice. To identify mediators of USP39 growth-promoting properties, we used luciferase reporter constructs under transcriptional control of various promoters specific to seven canonical cancer-associated pathways. Luciferase activity from a synthetic TEAD-dependent YAP/TAZ-responsive reporter, as a direct readout of the Hippo signaling pathway, was decreased by 92% in cells with USP39 knockdown, whereas the luciferase activities from the other six cancer pathways, including MAPK/ERK, MAPK/JNK, NFκB, Notch, TGFβ, and Wnt, remained unchanged. TAZ protein expression however was decreased independent of canonical Hippo signaling. Immunohistochemistry revealed a positive correlation between USP39 and TAZ proteins in orthotopic xenografts derived from modified glioma cells expressing USP39 shRNAs and primary human glioma samples (p < 0.05). Finally, loss of USP39 decreased TAZ pre-mRNA splicing efficiency in glioma cells in vitro, which led to reduced levels of TAZ protein. In summary, USP39 has oncogenic properties that increase TAZ protein levels by inducing maturation of its mRNA. USP39 therefore provides a novel therapeutic target for the treatment of human glioma.

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“…USP39 is essential for mitotic spindle checkpoint integrity and controls mRNA levels of Aurora B [4]. Down-regulation of USP39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells [21]. Knockdown of USP39 inhibited the growth of osteosarcoma cells and induced apoptosis in vitro [22].…”

Section: Discussionmentioning

confidence: 99%

USP39 regulates the cell cycle, survival, and growth of human leukemia cells

Liu

Yao

et al. 2019

Bioscience Reports

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Ubiquitin-specific peptidase 39 (USP39) is one member of the cysteine proteases of the USP family, which represents the largest group of DeUbiquitinases with more than 50 members in humans. The roles of USP39 in human cancer have been widely investigated. However, the roles of USP39 in human leukemia and the underlying mechanism remain unknown. Here we reported the function of USP39 in human leukemia. We observed that the expression of USP39 was up-regulated in human leukemia cells and the high expression of USP39 was correlated with poor survival of the patients with leukemia. Lentivirus-mediated knockdown of USP39 repressed the proliferation and colony formation of human leukemia cell lines HL-60 and Jurkat cells. Mechanism study showed that USP39 knockdown induced the arrest of cell cycle and apoptosis of leukemia cells. In addition, our microarray and bioinformatic analysis demonstrated that USP39 regulated diverse cellular signaling pathways that were involved in tumor biology, and several pivotal genes (IRF1, Caspase 8, and SP1) have been validated by quantitative real-time polymerase chain reaction. Knockdown or IRF1 partially restored the proliferation rate of leukemia cells with USP39 knockdown. Taken together, our findings implicate that USP39 promotes the development of human leukemia by regulating cell cycle, survival, and proliferation of the cells.

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Downregulation of ubiquitin-specific peptidase 39 suppresses the proliferation and induces the apoptosis of human colorectal cancer cells

Cited by 11 publications

References 24 publications

USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN–Induced Antiviral Immunity

USP39 Serves as a Deubiquitinase to Stabilize STAT1 and Sustains Type I IFN–Induced Antiviral Immunity

RNA splicing factor USP39 promotes glioma progression by inducing TAZ mRNA maturation

USP39 regulates the cell cycle, survival, and growth of human leukemia cells

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