A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription
Tekijät: Kaukonen R, Mai A, Georgiadou M, Saari M, De Franceschi N, Betz T, Sihto H, Ventelä S, Elo L, Jokitalo E, Westermarck J, Kellokumpu-Lehtinen P-L, Joensuu H, Grenman R, Ivaska J
Julkaisuvuosi: 2016
Journal: Nature Communications
Artikkelin numero: 12237
Vuosikerta: 7
Sivujen määrä: 15
ISSN: 2041-1723
DOI: https://doi.org/10.1038/ncomms12237
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.
