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

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. Synopsis SETDB1 controls EMT of breast epithelial and cancer cells. TGF‐β‐induced SETDB1 recruitment to Smad3 promotes H3K9 methylation and represses Smad3/4‐activated expression of SNAI1 , encoding an EMT master regulator. The histone lysine methyltransferase SETDB1 represses EMT, and during TGF‐β‐induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. TGF‐β‐induced Smad3 association with SETDB1 promotes H3K9 methylation of the Snai1 gene, and represses Smad3/4‐activated expression of Snail1. The mechanism of Smad3/SETDB1‐mediated histone methylation and transcription repression contrasts with Smad‐activated transcription in association with the H3K9 acetyltransferases CBP or p300. Graphical Abstract SETDB1 controls EMT of breast epithelial and cancer cells. TGF‐β‐induced SETDB1 recruitment to Smad3 promotes H3K9 methylation and represses Smad3/4‐activated expression of SNAI1 , encoding an EMT master regulator.