Opposing roles of ZEB1 in the cytoplasm and nucleus control cytoskeletal assembly and YAP1 activity
Yan Guo,
Xiaoqin Lu,
Yao Chen,
Geoff Clark,
John Trent,
Miriam Cuatrecasas,
Douglas Emery,
Zhao-Hui Song,
Julia Chariker,
Eric Rouchka,
Antonio Postigo,
Yongqing Liu,
Douglas C. Dean
Affiliations
Yan Guo
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Department of Hematology, The First Affiliated Hospital of Shandong First Medical University, Jinan 250014, China
Xiaoqin Lu
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Yao Chen
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Department of Ophthalmology, Xiangya Hospital of Central South University, Changsha, China
Geoff Clark
Department of Pharmacology, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
John Trent
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Miriam Cuatrecasas
Department of Pathology, Centro de Diagnóstico Biomédico (CDB) Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain
Douglas Emery
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Zhao-Hui Song
Department of Pharmacology, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Julia Chariker
Department of Computer Engineering and Computer Science, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Eric Rouchka
Department of Computer Engineering and Computer Science, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA
Antonio Postigo
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Group of Transcriptional Regulation of Gene Expression, IDIBAPS and University of Barcelona School of Medicine, 08036 Barcelona, Spain; ICREA, 08010 Barcelona, Spain; Corresponding author
Yongqing Liu
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Corresponding author
Douglas C. Dean
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA; Corresponding author
Summary: Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma (LUAD), driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migration and Yap1 nuclear transport. Tgfb causes turnover of the scaffold protein Rassf1a, which targets RhoA. Release of this RhoA inhibition in response to Tgfb overcomes Zeb1’s block of cytoskeleton assembly and frees it for nuclear transport. A ZEB1 nuclear transport signature highlights EMT progression, identifies dedifferentiated invasive/metastatic human LUADs, and predicts survival. Blocking Zeb1 nuclear transport with a small molecule identified in this study inhibits cytoskeleton assembly, cell migration, Yap1 nuclear transport, EMT, and precancerous-to-malignant transition.
