MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition
Robert J. Mobley,
Deepthi Raghu,
Lauren D. Duke,
Kayley Abell-Hart,
Jon S. Zawistowski,
Kyla Lutz,
Shawn M. Gomez,
Sujoy Roy,
Ramin Homayouni,
Gary L. Johnson,
Amy N. Abell
Affiliations
Robert J. Mobley
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Deepthi Raghu
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Lauren D. Duke
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Kayley Abell-Hart
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Jon S. Zawistowski
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Kyla Lutz
Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Shawn M. Gomez
Department of Biomedical Engineering and Curriculum in Bioinformatics and Computational Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Sujoy Roy
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Ramin Homayouni
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
Gary L. Johnson
Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Amy N. Abell
Department of Biological Sciences, University of Memphis, Memphis, TN 38152, USA
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.
