The EMT activator ZEB1 accelerates endosomal trafficking to establish a polarity axis in lung adenocarcinoma cells

Priyam Banerjee, Guan-Yu Xiao, Xiaochao Tan, Veronica J. Zheng, Lei Shi, Maria Neus Bota Rabassedas, Hou-fu Guo, Xin Liu, Jiang Yu, Lixia Diao, Jing Wang, William K. Russell, Jason Roszik, Chad J. Creighton and Jonathan M. Kurie ()
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Priyam Banerjee: The University of Texas MD Anderson Cancer Center
Guan-Yu Xiao: The University of Texas MD Anderson Cancer Center
Xiaochao Tan: The University of Texas MD Anderson Cancer Center
Veronica J. Zheng: The University of Texas MD Anderson Cancer Center
Lei Shi: The University of Texas MD Anderson Cancer Center
Maria Neus Bota Rabassedas: The University of Texas MD Anderson Cancer Center
Hou-fu Guo: University of Kentucky
Xin Liu: The University of Texas MD Anderson Cancer Center
Jiang Yu: The University of Texas MD Anderson Cancer Center
Lixia Diao: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
William K. Russell: University of Texas Medical Branch
Jason Roszik: The University of Texas MD Anderson Cancer Center
Chad J. Creighton: Baylor College of Medicine
Jonathan M. Kurie: The University of Texas MD Anderson Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Epithelial-to-mesenchymal transition (EMT) is a transcriptionally governed process by which cancer cells establish a front-rear polarity axis that facilitates motility and invasion. Dynamic assembly of focal adhesions and other actin-based cytoskeletal structures on the leading edge of motile cells requires precise spatial and temporal control of protein trafficking. Yet, the way in which EMT-activating transcriptional programs interface with vesicular trafficking networks that effect cell polarity change remains unclear. Here, by utilizing multiple approaches to assess vesicular transport dynamics through endocytic recycling and retrograde trafficking pathways in lung adenocarcinoma cells at distinct positions on the EMT spectrum, we find that the EMT-activating transcription factor ZEB1 accelerates endocytosis and intracellular trafficking of plasma membrane-bound proteins. ZEB1 drives turnover of the MET receptor tyrosine kinase by hastening receptor endocytosis and transport to the lysosomal compartment for degradation. ZEB1 relieves a plus-end-directed microtubule-dependent kinesin motor protein (KIF13A) and a clathrin-associated adaptor protein complex subunit (AP1S2) from microRNA-dependent silencing, thereby accelerating cargo transport through the endocytic recycling and retrograde vesicular pathways, respectively. Depletion of KIF13A or AP1S2 mitigates ZEB1-dependent focal adhesion dynamics, front-rear axis polarization, and cancer cell motility. Thus, ZEB1-dependent transcriptional networks govern vesicular trafficking dynamics to effect cell polarity change.

Date: 2021
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DOI: 10.1038/s41467-021-26677-y

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