Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

Kobayashi, Tamae; Masoumi, Katarzyna Chmielarska; Massoumi, Ramin

doi:10.1038/onc.2014.159

Cited by 34 publications

(27 citation statements)

References 42 publications

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“…One of the nine genes we confirmed to be repressed by both MYCN and TFAP4, CYLD, a deubiquitinating enzyme that negatively regulates NF-κB activation [24], is a well-established tumor suppressor gene, and loss of CYLD expression has been observed in various human cancer types [25]. Our findings that high CYLD levels are predictive for good prognosis in neuroblastoma (Supplementary Figure S4) are in agreement with a recent report showing that higher CYLD expression in neuroblastoma patient samples correlated with better survival and early tumor stages, and CYLD expression was significantly lower in MYCN -amplified tumors [26]. In addition to CYLD , knockdown of DENND5A in MDCKII cells was reported to lead to an increase in cell migration [27], while SSU72 was shown to be downregulated in the progression to hormone-refractory prostate cancer [28].…”

Section: Discussionsupporting

confidence: 92%

MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

Xue

Gherardi

et al. 2016

Oncotarget

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Amplification of the MYCN oncogene, a member of the MYC family of transcriptional regulators, is one of the most powerful prognostic markers identified for poor outcome in neuroblastoma, the most common extracranial solid cancer in childhood. While MYCN has been established as a key driver of malignancy in neuroblastoma, the underlying molecular mechanisms are poorly understood. Transcription factor activating enhancer binding protein-4 (TFAP4) has been reported to be a direct transcriptional target of MYC. We show for the first time that high expression of TFAP4 in primary neuroblastoma patients is associated with poor clinical outcome. siRNA-mediated suppression of TFAP4 in MYCN-expressing neuroblastoma cells led to inhibition of cell proliferation and migration. Chromatin immunoprecipitation assay demonstrated that TFAP4 expression is positively regulated by MYCN. Microarray analysis identified genes regulated by both MYCN and TFAP4 in neuroblastoma cells, including Phosphoribosyl-pyrophosphate synthetase-2 (PRPS2) and Syndecan-1 (SDC1), which are involved in cancer cell proliferation and metastasis. Overall this study suggests a regulatory circuit in which MYCN by elevating TFAP4 expression, cooperates with it to control a specific set of genes involved in tumor progression. These findings highlight the existence of a MYCN-TFAP4 axis in MYCN-driven neuroblastoma as well as identifying potential therapeutic targets for aggressive forms of this disease.

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Section: Discussionsupporting

confidence: 92%

MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

Xue

Gherardi

et al. 2016

Oncotarget

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“…The activity of the NF-kB-associated DUB CYLD is negatively affected by both phosphorylation and sumoylation [78,79], while sumoylation also impedes USP25 activity. This multidomain DUB contains UBDs that are required for efficient polyubiquitin hydrolysis.…”

Section: Post-translational Modificationsmentioning

confidence: 98%

Layers of DUB regulation

Sahtoe

Sixma

2015

Trends in Biochemical Sciences

114

101

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“…This modification inhibits polyubiquitin hydrolysis by USP25, most likely by blocking the binding of ubiquitin to its UIM. Similarly, SUMOylation of CYLD inhibits CYLD-mediated deubiquitylation of components of the NF-κB signalling pathway (Kobayashi et al, 2015).…”

Section: Ubiquitylation and Sumoylationmentioning

confidence: 99%

Mechanisms of regulation and diversification of deubiquitylating enzyme function

Leznicki

Kulathu

2017

Journal of Cell Science

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Deubiquitylating (or deubiquitinating) enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this post-translational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes.This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: 'Exploitation of the host cell ubiquitin machinery by microbial effector proteins' by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985-1996. 'Cell scientist to watch -Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981-1983.

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Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells

Cited by 34 publications

References 42 publications

MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

MYCN promotes neuroblastoma malignancy by establishing a regulatory circuit with transcription factor AP4

Layers of DUB regulation

Mechanisms of regulation and diversification of deubiquitylating enzyme function

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