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SKP2 is a direct transcriptional target of MYCN and a potential therapeutic target in neuroblastoma

Lookup NU author(s): Laura Evans, Dr Lindi Chen, Dr Elaine Willmore, Professor Herbie Newell, Professor Deborah Tweddle

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Abstract

SKP2 is the substrate recognition subunit of the ubiquitin ligase complex which targets p27(KIP1) for degradation. Induced at the G(1)/S transit of the cell cycle, SKP2 is frequently overexpressed in human cancers and contributes to malignancy. We previously identified SKP2 as a possible MYCN target gene and hence hypothesise that SKP2 is a potential therapeutic target in MYCN amplified disease. A positive correlation was identified between MYCN activity and SKP2 mRNA expression in Tet21N MYCN-regulatable cells and a panel of MYCN amplified and non-amplified neuroblastoma cell lines. In chromatin immunoprecipitation and reporter gene assays, MYCN bound directly to E-boxes within the SKP2 promoter and induced transcriptional activity which was decreased by the removal of MYCN and E-box mutation. Although SKP2 knockdown inhibited cell growth in both MYCN amplified and non-amplified cells, cell cycle arrest and apoptosis were induced only in non-MYCN amplified neuroblastoma cells. In conclusion these data identify SKP2 as a direct transcriptional target of MYCN and supports SKP2 as a potential therapeutic target in neuroblastoma. (C) 2015 Elsevier Ireland Ltd. All rights reserved.


Publication metadata

Author(s): Evans L, Chen L, Milazzo G, Gherardi S, Perini G, Willmore E, Newell DR, Tweddle DA

Publication type: Article

Publication status: Published

Journal: Cancer Letters

Year: 2015

Volume: 363

Issue: 1

Pages: 37-45

Print publication date: 10/07/2015

Online publication date: 02/04/2015

Acceptance date: 28/03/2015

ISSN (print): 0304-3835

ISSN (electronic): 1872-7980

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.canlet.2015.03.044

DOI: 10.1016/j.canlet.2015.03.044


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