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

Author

Listed:
  • 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
    Head and Neck Surgery, Turku University and Turku University Hospital)

  • Laura Elo

    (Centre for Biotechnology, University of Turku
    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
    Helsinki University Central Hospital)

  • Reidar Grenman

    (Head and Neck Surgery, Turku University and Turku University Hospital)

  • Johanna Ivaska

    (Centre for Biotechnology, University of Turku
    University of Turku)

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.

Suggested Citation

  • 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-Le, 2016. "Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12237
    DOI: 10.1038/ncomms12237
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    Cited by:

    1. Richard J. Hewitt & Franz Puttur & David C. A. Gaboriau & Frédéric Fercoq & Maryline Fresquet & William J. Traves & Laura L. Yates & Simone A. Walker & Philip L. Molyneaux & Samuel V. Kemp & Andrew G., 2023. "Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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