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EMBO Rep. 2018 Jan;19(1):135-155. doi: 10.15252/embr.201744250. Epub 2017 Dec 12.

Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition.

Author information

1
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA, USA dan.du@ucsf.edu rik.derynck@ucsf.edu.
2
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA, USA.
3
Department of Cell and Tissue Biology, University of California at San Francisco, San Francisco, CA, USA.
4
Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
5
Department of Cellular and Molecular Pharmacology, Biophysics Graduate Program University of California at San Francisco, San Francisco, CA, USA.
6
Department of Research Pathology, Genentech Inc., South San Francisco, CA, USA.
7
Department of Anatomy, University of California at San Francisco, San Francisco, CA, USA.

Abstract

During epithelial-mesenchymal transition (EMT), reprogramming of gene expression is accompanied by histone modifications. Whether EMT-promoting signaling directs functional changes in histone methylation has not been established. We show here that the histone lysine methyltransferase SETDB1 represses EMT and that, during TGF-β-induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. SETDB1 also controls stem cell generation, cancer cell motility, invasion, metastatic dissemination, as well as sensitivity to certain cancer drugs. These functions may explain the correlation of breast cancer patient survival with SETDB1 expression. At the molecular level, TGF-β induces SETDB1 recruitment by Smad3, to repress Smad3/4-activated transcription of SNAI1, encoding the EMT "master" transcription factor SNAIL1. Suppression of SNAIL1-mediated gene reprogramming by SETDB1 occurs through H3K9 methylation at the SNAI1 gene that represses its H3K9 acetylation imposed by activated Smad3/4 complexes. SETDB1 therefore defines a TGF-β-regulated balance between histone methylation and acetylation that controls EMT.

KEYWORDS:

TGF‐β signaling; cancer cell dissemination; cancer drug resistance; epithelial stem cells; histone methylation

PMID:
29233829
PMCID:
PMC5757214
DOI:
10.15252/embr.201744250
[Indexed for MEDLINE]
Free PMC Article

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