title: Epigenetic silencing of serine protease HTRA1 drives polyploidy.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Schmidt
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Irle
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Kamilla
authors.initials: K
authors.lastname: Ripkens
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Vanda
authors.initials: V
authors.lastname: Lux
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Nelles
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Johannes
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Parry
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Greenow
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Amir
authors.affiliation: Department of Biochemistry and Biophysics, Section of Pathology, Second University of Naples, 80100, Naples, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Campioni
authors.affiliation: Department of Biochemistry and Biophysics, Section of Pathology, Second University of Naples, 80100, Naples, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.affiliation: Division of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan.
authors.forename: Chio
authors.initials: C
authors.lastname: Oka
authors.affiliation: Division of Gene Function in Animals, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara, 630-0192, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawaichi
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
authors.affiliation: Centre for Medical Biotechnology, Faculty of Biology and Geography, University Duisburg-Essen, Universitaetsstrasse, D-45117, Essen, Germany. michael.ehrmann@uni-due.de.|School of Biosciences, Cardiff University, Cardiff, CF10 3US, UK. michael.ehrmann@uni-due.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D011123:Polyploidy; D011401:Promoter Regions, Genetic; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C489325:MBD2 protein, human; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases
keywords: HTRA1; MDB2; serine protease