Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

Quick, Laura; Young, Robert A.; Henrich, Ian C.; Wang, Xiaoke; Asmann, Yan W.; Oliveira, André M.; Chou, Margaret M.

doi:10.1158/0008-5472.can-15-2391

Cited by 34 publications

(41 citation statements)

References 49 publications

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“…USP6 functions in remodeling of the cytoskeleton and extracellular matrix, inflammatory response, cell signaling, cellular trafficking, and protein turnover, 23,27,[36][37][38][39][40][41][42][43][44] but its specific role in tumorigenesis is not entirely clear. More recently, Quick et al 45 reported that Jak1-STAT3 signaling has an essential role in USP6-related tumorigenesis, while Madan et al 46 suggested a role for Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

et al. 2017

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Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH. We sought to further characterize such tumors using molecular diagnostic assays. A novel RT-PCR assay was designed to detect the two known MYH9-USP6 fusion types in formalin-fixed paraffin-embedded and frozen tissue, and a break-apart FISH assay was designed to detect USP6 rearrangement. Twenty-six cases of nodular fasciitis diagnosed between 2002 and 2013 were retrieved from the pathology files of our institutions and were confirmed to be positive by FISH and/or RT-PCR. Seven samples showed USP6 rearrangement by FISH but were negative for MYH9-USP6 fusion by RT-PCR; these cases were subjected to a next-generation sequencing assay utilizing anchored multiplex PCR technology. This assay targets a single partner gene associated with fusions in bone and soft tissue tumors for agnostic detection of gene fusion partners. Novel fusion partners were identified in all seven cases and confirmed by RT-PCR. Structurally, all fusions consisted of the juxtaposition of the entire coding region of USP6 with the promoter of the partner gene, driving increased USP6 expression. This study confirms the neoplastic nature of nodular fasciitis, defines additional pathogenic fusion partners, and adds to the growing body of literature on USP6-associated neoplasia. Given the diagnostic challenges of these tumors, molecular assays can be useful ancillary tools; however, the prevalence of promoter swapping must be recognized when interpreting results.

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Section: Discussionmentioning

confidence: 99%

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

et al. 2017

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“…Therefore, studies identifying the downstream effectors of USP6 will improve our knowledge of and ability to cure these diseases. Actually, two novel genes, the Frizzled and JAK1 genes, were recently identified as USP6 substrates (20,21). Using a DUB library, we identified the transcription factor c-Jun as a novel substrate of USP6.…”

Section: Discussionmentioning

confidence: 99%

“…Data sources and preprocessing. The three data sets (GSE52252, GSE78991, and GSE18229) used in this study were downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/) (21,(32)(33)(34). Differentially expressed (DE) genes were identified and compared among 9 nodular fasciitis tumors with USP6 translocation in data set GSE78991 and 27 other tumors in data set GSE52252.…”

Section: Methodsmentioning

confidence: 99%

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Ubiquitin-Specific Protease USP6 Regulates the Stability of the c-Jun Protein

Liu

Yang

et al. 2018

Molecular and Cellular Biology

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The c- gene encodes a transcription factor that has been implicated in many physiological and pathological processes. c-Jun is a highly unstable protein that is degraded through a ubiquitination/proteasome-dependent mechanism. However, the deubiquitinating enzyme (DUB) that regulates the stability of the c-Jun protein requires further investigation. Here, by screening a DUB expression library, we identified ubiquitin-specific protease 6 (USP6) and showed that it regulates the stability of the c-Jun protein in a manner depending on its enzyme activity. USP6 interacts with c-Jun and antagonizes its ubiquitination. USP6 overexpression upregulates the activity of the downstream signaling pathway mediated by c-Jun/AP-1 and promotes cell invasion. Moreover, many aberrant genes that are upregulated in translocated nodular fasciitis are great potential targets regulated by c-Jun. Based on our data, USP6 is an enzyme that deubiquitinates c-Jun and regulates its downstream cellular functions.

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“…Previous reports on the cellular role and targets of USP6 are sparse, although it has been suggested to deubiquitylate Frizzled and promote Wnt signalling (18), and to deubiquitylate Jak1 causing activation of the STAT3 signalling pathway (19). USP6 has also been demonstrated to regulate the stability of the c-Jun transcription factor (20), and high USP6 protein expression has been observed in bone and soft tissue tumours (21).…”

Section: Discussionmentioning

confidence: 99%

Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionising radiation and complex DNA damage

Carter

Nickson

Thompson

et al. 2018

Preprint

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Purpose: Ionising radiation, particular high linear energy transfer (LET) radiation, can induce complex DNA damage (CDD) where two or more DNA lesions are induced in close proximity which contributes significantly to the cell killing effects. However knowledge of the enzymes and mechanisms involved in co-ordinating the recognition and processing of CDD in cellular DNA are currently lacking. Methods and Materials:An siRNA screen of deubiquitylation enzymes was conducted in HeLa cells irradiated with high-LET -particles or protons, versus low-LET protons and xrays, and cell survival monitored by clonogenic assays. Candidates whose depletion led to decreased cell survival specifically in response to high-LET radiation were validated in both HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells, and the association with CDD repair was confirmed by using an enzyme modified neutral comet assay. Results:Depletion of USP6 decreased cell survival specifically following high-LET αparticles and protons, but not by low-LET protons or x-rays. USP6 depletion caused cell cycle arrest and a deficiency in CDD repair mediated through instability of poly(ADP-ribose) polymerase-1 (PARP-1). This phenotype was mimicked using the PARP inhibitor olaparib.Conclusion: USP6 controls cell survival in response to high-LET radiation by stabilising PARP-1 protein levels which is essential for CDD repair. We also describe synergy between CDD induced by high-LET protons and PARP inhibition in effective cancer cell killing.

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Jak1–STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis

Cited by 34 publications

References 49 publications

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

USP6 activation in nodular fasciitis by promoter-swapping gene fusions

Ubiquitin-Specific Protease USP6 Regulates the Stability of the c-Jun Protein

Characterisation of deubiquitylating enzymes in the cellular response to high-LET ionising radiation and complex DNA damage

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