Epigenetic silencing of serine protease HTRA1 drives polyploidy.

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.

• Authors: Nina Schmidt, Inga Irle, Kamilla Ripkens, Vanda Lux, Jasmin Nelles, Christian Johannes, Lee Parry, Kirsty Greenow, Sarah Amir, Mara Campioni, Alfonso Baldi, Chio Oka, Masashi Kawaichi, Alan R Clarke, Michael Ehrmann
• Journal: BMC cancer (BMC Cancer) Vol. 16 Pg. 399 (07 07 2016) ISSN: 1471-2407 [Electronic] England
• PMID: 27388476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MBD2 protein, human
• High-Temperature Requirement A Serine Peptidase 1
• HtrA1 protein, human
• Serine Endopeptidases

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• Cells, Cultured
• Centrosome (metabolism)
• Colonic Neoplasms (genetics, pathology)
• DNA Methylation
• DNA-Binding Proteins (metabolism)
• Down-Regulation
• Epigenesis, Genetic
• Fibroblasts (cytology, metabolism)
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• High-Temperature Requirement A Serine Peptidase 1
• Humans
• Mice
• Neoplasm Transplantation
• Polyploidy
• Promoter Regions, Genetic
• Serine Endopeptidases (genetics)