1. Academic Validation
  2. Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation

Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation

  • J Exp Med. 2017 Aug 7;214(8):2349-2368. doi: 10.1084/jem.20170724.
Dong Eun Kim 1 Maria-Giuseppina Procopio 1 Soumitra Ghosh 1 Seung-Hee Jo 2 Sandro Goruppi 2 Francesco Magliozzi 1 Pino Bordignon 1 Victor Neel 3 Paolo Angelino 4 G Paolo Dotto 5 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Lausanne, Épalinges, Switzerland.
  • 2 Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA.
  • 3 Department of Dermatology, Massachusetts General Hospital, Boston, MA.
  • 4 Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • 5 Department of Biochemistry, University of Lausanne, Épalinges, Switzerland paolo.dotto@unil.ch.
Abstract

Cancer-associated fibroblasts (CAFs) are important for tumor initiation and promotion. CSL, a transcriptional repressor and Notch mediator, suppresses CAF activation. Like CSL, ATF3, a stress-responsive transcriptional repressor, is down-modulated in skin Cancer stromal cells, and Atf3 knockout mice develop aggressive chemically induced skin tumors with enhanced CAF activation. Even at low basal levels, ATF3 converges with CSL in global chromatin control, binding to few genomic sites at a large distance from target genes. Consistent with this mode of regulation, deletion of one such site 2 Mb upstream of IL6 induces expression of the gene. Observed changes are of translational significance, as bromodomain and extra-terminal (BET) inhibitors, unlinking activated chromatin from basic transcription, counteract the effects of ATF3 or CSL loss on global gene expression and suppress CAF tumor-promoting properties in an in vivo model of squamous cancer-stromal cell expansion. Thus, ATF3 converges with CSL in negative control of CAF activation with epigenetic changes amenable to cancer- and stroma-focused intervention.

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