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

Nat Commun. 2016 Aug 4;7:12237. doi: 10.1038/ncomms12237.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer-Associated Fibroblasts / metabolism
  • Cancer-Associated Fibroblasts / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chickens
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / ultrastructure
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Mechanotransduction, Cellular*
  • Neoplasms / genetics*
  • Neoplasms / pathology*
  • Stromal Cells / cytology
  • Stromal Cells / metabolism
  • Transcription Factors
  • Transcription, Genetic*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Transcription Factors
  • WWTR1 protein, human
  • Jumonji Domain-Containing Histone Demethylases
  • KDM3A protein, human