MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition

Cell Rep. 2017 Mar 7;18(10):2387-2400. doi: 10.1016/j.celrep.2017.02.030.


The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TSKI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TSKI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TSKI4 cells restores epithelial features, including cell-cell adhesion and barrier formation. These data define a role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes.

Keywords: HDAC6; MAP3K4; chromatin remodelers; development; epigenetics; epithelial to mesenchymal transition; histone acetylation; histone deacetylase; tight junctions; trophoblast stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Differentiation
  • Cell Nucleus / metabolism
  • Chromatin / metabolism*
  • Epithelial-Mesenchymal Transition* / genetics
  • Histone Deacetylase 6 / metabolism*
  • MAP Kinase Kinase Kinase 4 / metabolism
  • Mice
  • Phenotype
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Proteolysis
  • Stem Cells / cytology*
  • Tight Junction Proteins / metabolism
  • Trophoblasts / metabolism*
  • Ubiquitination


  • Chromatin
  • Tight Junction Proteins
  • MAP Kinase Kinase Kinase 4
  • Map3k4 protein, mouse
  • Hdac6 protein, mouse
  • Histone Deacetylase 6