The deubiquitinating enzyme USP5 promotes pancreatic cancer via modulating cell cycle regulators

Kaistha, Brajesh P.; Krattenmacher, Anja; Fredebohm, Johannes; Schmidt, Harald; Behrens, Diana; Widder, Miriam; Hackert, Thilo; Strobel, Oliver; Hoheisel, Jörg D.; Gress, Thomas M.; Buchholz, Malte

doi:10.18632/oncotarget.19882

Cited by 32 publications

(44 citation statements)

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“…The pooled shRNA library is a valuable tool for gene screening. It has identified NQQ1 as a potential drug target for host‐directed tuberculosis therapy, ATP1A1 as a gene that regulates aurilide B cytotoxicity, and the deubiquitinating enzyme, USP5, which modulates cell cycle regulators . The shRNA screening system has also identified HIF1α as a TERT regulator using mouse ES cells …”

Section: Discussionmentioning

confidence: 99%

“…It has identified NQQ1 as a potential drug target for host-directed tuberculosis therapy, ATP1A1 as a gene that regulates aurilide B cytotoxicity, and the deubiquitinating enzyme, USP5, which modulates cell cycle regulators. [34][35][36] The shRNA screening system has also identified HIF1α as a TERT regulator using mouse ES cells. 37 In this study in a HCC cell line, we identified two genes, C15orf55 and C7orf43, as activators of TERT transcription through SP1 and YAP1, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Identification of genes involved in the regulation of TERT in hepatocellular carcinoma

et al. 2019

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Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome‐wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55‐ and C7orf43‐responsive sites exist between base pairs −58 and +36 and −169 and −59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes‐associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non‐tumor tissues, compared to normal liver tissues from non‐HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of genes involved in the regulation of TERT in hepatocellular carcinoma

et al. 2019

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“…USP5 have been reported as an oncoprotein in diverse cancers including myeloma 4 , non-small cell lung cancer 5 , hepatocellular carcinoma 6 , colorectal cancer 7 , ovarian cancer 8 and pancreatic cancer 9 . USP5 have been studied in the development of pancreatic cancer 9 , 10 . However, the role of USP5 in pancreatic cancer still needs to be studied.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin specific peptidase 5 enhances STAT3 signaling and promotes migration and invasion in Pancreatic Cancer

Lian¹,

Liu²,

Guan³

et al. 2020

J. Cancer

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Purpose: Ubiquitin specific peptidase 5 (USP5) has been reported to promote the progression of several malignant tumors. It may affect cancer development via modulating cell cycle and colony formation. In pancreatic cancer, the biological function of USP5, especially in migration and invasion remains unclear. Methods: USP5 protein expression levels in primary pancreatic cancer and lymph node metastasis tissues were detected using immunohistochemistry (IHC). χ 2 test, Kaplan-Meier analysis, univariate and multivariate analyses were used to evaluate the relationship between USP5 expression and clinicopathological feature. RT-qPCR were carried out to quantitate the mRNA expression levels of USP5 in pancreatic cancer cell lines. CCK8 and Colony formation assay were performed to prove how USP5 works in proliferation. Evaluation of tumor metastasis was made by Transwell and wound healing assay. EMT and STAT3 signaling related markers were detected by western blot. Results: (1) USP5 protein expression levels were related to tumor differentiation, CEA and CA19-9 level. (2) Univariate and multivariate analyses showed that high USP5 expression is an unfavorable prognostic factor for pancreatic cancer. Kaplan-Meier analysis directly indicated that patients with high USP5 expression had shorter overall survival. (3) Increased USP5 expression is related to pancreatic cancer in both proliferation and metastasis. (4) USP5 was proved to mediate STAT3 signaling in pancreatic cancer cells. Conclusions: The results suggest that USP5 is highly expressed and might have clinical significance for pancreatic cancer patients. High USP5 expression promotes both progression and metastasis by activating STAT3 signaling. Thus, USP5 might be a potential target in pancreatic cancer treatment.

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“…USP5 has been associated with tumorigenesis [15][16][17][18][19] , neurodegeneration [20][21][22] , and viral infections 23,24 . In addition, USP5 plays a role in regulation of ubiquitin levels in DNA damage repair 25 and stress granules 26 .…”

Section: Introductionmentioning

confidence: 99%

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

Mann

Franzoni

Freitas

et al. 2019

Preprint

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USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease. Corresponding Authors Author Contributions M.M. and M.S. wrote the manuscript. I.F. and R.F.F. completed preliminary docking studies. R.H., and M.M. performed the crystallographic calculations and model refinement for X-ray crystal structures with 1, 5, and 7. W.T. performed the crystallographic calculations and model refinement of X-ray structure with compound 21. M.M. and S.H tested compounds. M.M. completed hit expansion. C.H.A, R.H. and M.S. advised throughout the project. Notes:The authors declare no competing financial interest.

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The deubiquitinating enzyme USP5 promotes pancreatic cancer via modulating cell cycle regulators

Cited by 32 publications

References 44 publications

Identification of genes involved in the regulation of TERT in hepatocellular carcinoma

Identification of genes involved in the regulation of TERT in hepatocellular carcinoma

Ubiquitin specific peptidase 5 enhances STAT3 signaling and promotes migration and invasion in Pancreatic Cancer

Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

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