ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer

Roxsan Manshouri, Etienne Coyaud, Samrat T. Kundu, David H. Peng, Sabrina A. Stratton, Kendra Alton, Rakhee Bajaj, Jared J. Fradette, Rosalba Minelli, Michael D. Peoples, Alessandro Carugo, Fengju Chen, Christopher Bristow, Jeffrey J. Kovacs, Michelle C. Barton, Tim Heffernan, Chad J. Creighton, Brian Raught and Don L. Gibbons ()
Additional contact information
Roxsan Manshouri: The University of Texas MD Anderson Cancer Center
Etienne Coyaud: University of Toronto
Samrat T. Kundu: The University of Texas MD Anderson Cancer Center
David H. Peng: The University of Texas MD Anderson Cancer Center
Sabrina A. Stratton: The University of Texas MD Anderson Cancer Center
Kendra Alton: The University of Texas MD Anderson Cancer Center
Rakhee Bajaj: The University of Texas MD Anderson Cancer Center
Jared J. Fradette: The University of Texas MD Anderson Cancer Center
Rosalba Minelli: The University of Texas MD Anderson Cancer Center
Michael D. Peoples: The University of Texas MD Anderson Cancer Center
Alessandro Carugo: The University of Texas MD Anderson Cancer Center
Fengju Chen: Baylor College of Medicine
Christopher Bristow: The University of Texas MD Anderson Cancer Center
Jeffrey J. Kovacs: The University of Texas MD Anderson Cancer Center
Michelle C. Barton: The University of Texas MD Anderson Cancer Center
Tim Heffernan: The University of Texas MD Anderson Cancer Center
Chad J. Creighton: Baylor College of Medicine
Brian Raught: University of Toronto
Don L. Gibbons: The University of Texas MD Anderson Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, due in part to the propensity of lung cancer to metastasize. Aberrant epithelial-to-mesenchymal transition (EMT) is a proposed model for the initiation of metastasis. During EMT cell-cell adhesion is reduced allowing cells to dissociate and invade. Of the EMT-associated transcription factors, ZEB1 uniquely promotes NSCLC disease progression. Here we apply two independent screens, BioID and an Epigenome shRNA dropout screen, to define ZEB1 interactors that are critical to metastatic NSCLC. We identify the NuRD complex as a ZEB1 co-repressor and the Rab22 GTPase-activating protein TBC1D2b as a ZEB1/NuRD complex target. We find that TBC1D2b suppresses E-cadherin internalization, thus hindering cancer cell invasion and metastasis.

Date: 2019
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DOI: 10.1038/s41467-019-12832-z

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