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BMC Cancer. 2016 Jul 7;16:399. doi: 10.1186/s12885-016-2425-8.

Epigenetic silencing of serine protease HTRA1 drives polyploidy.

Author information

1
Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
2
School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK.
3
Department of Biochemistry and Biophysics, Section of Pathology, Second University of Naples, 80100, Naples, Italy.
4
Division of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan.
5
Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany. michael.ehrmann@uni-due.de.
6
School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK. michael.ehrmann@uni-due.de.

Abstract

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.

KEYWORDS:

HTRA1; MDB2; serine protease

PMID:
27388476
PMCID:
PMC4936022
DOI:
10.1186/s12885-016-2425-8
[Indexed for MEDLINE]
Free PMC Article

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