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J. Exp. Med., Published July 6, 2017 | DOI: 10.1084/jem.20170724
Convergent roles of ATF3 and CSL in chromatin control of cancer-associated fibroblast activation
Dong Eun Kim,1 * Maria-Giuseppina Procopio,1 * Soumitra Ghosh,1* Seung-HeeJo,2 Sandro Goruppi,2 Francesco Magliozzi,1 Pino Bordignon,1 Victor Neel,3 Paolo Angelino,4 and G. Paolo Dotto1,2
1 Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
1 Department of Biochemistry, University of Lausanne, Epalinges, 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
*D.E. Kim, M.-G. Procopio, and S. Ghosh contributed equally to this paper.
*D.E. Kim, M.-G. Procopio, and S. Ghosh contributed equally to this paper.
Correspondence to G. Paolo Dotto
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.
논문정보
- Research article
- 2017년 07월 (BRIC 등록일 2017-09-12)
- 국외 연구진
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