title: Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription.
abstract: Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal-not cancer-stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Kaukonen
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Anja
authors.initials: A
authors.lastname: Mai
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiadou
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Saari
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Franceschi
authors.affiliation: Institute of Cell Biology, Center for Molecular Biology of Inflammation, 48149 Muenster, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Betz
authors.affiliation: Laboratory of Molecular Oncology, Translational Cancer Biology Program, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Harri
authors.identifier: 0000-0001-5265-5509
authors.initials: H
authors.lastname: Sihto
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.|Department of Otorhinolaryngology, Head and Neck Surgery, Turku University and Turku University Hospital, 20521 Turku, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Ventelä
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.|Department of Mathematics and Statistics, University of Turku, 20520, Turku, Finland.
authors.forename: Laura
authors.initials: L
authors.lastname: Elo
authors.affiliation: Institute of Biotechnology, Electron Microscopy Unit University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Eija
authors.initials: E
authors.lastname: Jokitalo
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.affiliation: Department of Oncology, Tampere University Hospital, 36280 Tampere, Finland.
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Laboratory of Molecular Oncology, Translational Cancer Biology Program, University of Helsinki, 00290 Helsinki, Finland.|Department of Oncology, Helsinki University Central Hospital, 00029 Helsinki, Finland.
authors.forename: Heikki
authors.identifier: 0000-0003-0281-2507
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Turku University and Turku University Hospital, 20521 Turku, Finland.
authors.forename: Reidar
authors.initials: R
authors.lastname: Grenman
authors.affiliation: Centre for Biotechnology, University of Turku, 20520 Turku, Finland.|Department of Biochemistry and Food Chemistry, University of Turku, 20520 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002645:Chickens; D005109:Extracellular Matrix / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors; D014158:Transcription, Genetic; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human