Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription

Riina Kaukonen, Anja Mai, Maria Georgiadou, Markku Saari, Nicola De Franceschi, Timo Betz, Harri Sihto, Sami Ventelä, Laura Elo, Eija Jokitalo, Jukka Westermarck, Pirkko-Liisa Kellokumpu-Lehtinen, Heikki Joensuu, Reidar Grenman and Johanna Ivaska ()
Additional contact information
Riina Kaukonen: Centre for Biotechnology, University of Turku
Anja Mai: Centre for Biotechnology, University of Turku
Maria Georgiadou: Centre for Biotechnology, University of Turku
Markku Saari: Centre for Biotechnology, University of Turku
Nicola De Franceschi: Centre for Biotechnology, University of Turku
Timo Betz: Institute of Cell Biology, Center for Molecular Biology of Inflammation
Harri Sihto: Laboratory of Molecular Oncology, Translational Cancer Biology Program, University of Helsinki
Sami Ventelä: Centre for Biotechnology, University of Turku
Laura Elo: Centre for Biotechnology, University of Turku
Eija Jokitalo: Institute of Biotechnology, Electron Microscopy Unit University of Helsinki
Jukka Westermarck: Centre for Biotechnology, University of Turku
Pirkko-Liisa Kellokumpu-Lehtinen: Tampere University Hospital
Heikki Joensuu: Laboratory of Molecular Oncology, Translational Cancer Biology Program, University of Helsinki
Reidar Grenman: Head and Neck Surgery, Turku University and Turku University Hospital
Johanna Ivaska: Centre for Biotechnology, University of Turku

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12237

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