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Epigenetic silencing of serine protease HTRA1 drives polyploidy

Schmidt, Nina, Irle, Inga, Ripkens, Kamilla, Lux, Vanda, Nelles, Jasmin, Johannes, Christian, Parry, Lee, Greenow, Kirsty, Amir, Sarah, Campioni, Mara, Baldi, Alfonso, Oka, Chio, Kawaichi, Masashi, Clarke, Alan R. and Ehrmann, Michael 2016. Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC Cancer 16 , 399. 10.1186/s12885-016-2425-8

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Background: Increased numbers and improperly positioned centrosomes, aneuploidy or polyploidy, and chromosomal instability are frequently observed characteristics of cancer cells. While some aspects of these events and the checkpoint mechanisms are well studied, not all players have yet been identified. As the role of proteases other than the proteasome in tumorigenesis is an insufficiently addressed question, we investigated the epigenetic control of the widely conserved protease HTRA1 and the phenotypes of deregulation. Methods: Mouse embryonal fibroblasts and HCT116 and SW480 cells were used to study the mechanism of epigenetic silencing of HTRA1. In addition, using cell biological and genetic methods, the phenotypes of downregulation of HTRA1 expression were investigated. Results: HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2. On the cellular level, HTRA1 depletion causes multiple phenotypes including acceleration of cell growth, centrosome amplification and polyploidy in SW480 colon adenocarcinoma cells as well as in primary mouse embryonic fibroblasts (MEFs). Conclusions: Downregulation of HTRA1 causes a number of phenotypes that are hallmarks of cancer cells suggesting that the methylation state of the HtrA1 promoter may be used as a biomarker for tumour cells or cells at risk of transformation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: BMC (part of Springer Nature)
ISSN: 1471-2407
Date of First Compliant Deposit: 12 July 2016
Date of Acceptance: 27 June 2016
Last Modified: 31 Mar 2020 10:45

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