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; Don L. Gibbons

doi:10.1038/s41467-019-12832-z

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, Don L. Gibbons

Research output: Contribution to journal › Article › peer-review

62 Scopus citations

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.

Original language	English (US)
Article number	5125
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12832-z
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-12832-z

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Manshouri, R., Coyaud, E., Kundu, S. T., Peng, D. H., Stratton, S. A., Alton, K., Bajaj, R., Fradette, J. J., Minelli, R., Peoples, M. D., Carugo, A., Chen, F., Bristow, C., Kovacs, J. J., Barton, M. C., Heffernan, T., Creighton, C. J., Raught, B., & Gibbons, D. L. (2019). ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer. Nature communications, 10(1), Article 5125. https://doi.org/10.1038/s41467-019-12832-z

Manshouri, R, Coyaud, E, Kundu, ST, Peng, DH, Stratton, SA, Alton, K, Bajaj, R, Fradette, JJ, Minelli, R, Peoples, MD, Carugo, A, Chen, F, Bristow, C, Kovacs, JJ, Barton, MC, Heffernan, T, Creighton, CJ, Raught, B & Gibbons, DL 2019, 'ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer', Nature communications, vol. 10, no. 1, 5125. https://doi.org/10.1038/s41467-019-12832-z

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

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.",

author = "Roxsan Manshouri and Etienne Coyaud and Kundu, {Samrat T.} and Peng, {David H.} and Stratton, {Sabrina A.} and Kendra Alton and Rakhee Bajaj and Fradette, {Jared J.} and Rosalba Minelli and Peoples, {Michael D.} and Alessandro Carugo and Fengju Chen and Christopher Bristow and Kovacs, {Jeffrey J.} and Barton, {Michelle C.} and Tim Heffernan and Creighton, {Chad J.} and Brian Raught and Gibbons, {Don L.}",

note = "Funding Information: This work was supported by the NIH R37 CA214609-01A1, CPRIT-MIRA RP160652-P3, and Rexanna{\textquoteright}s Foundation for Fighting Lung Cancer to D.L.G., CPRIT multi-investigator award RP120713 C2 (C.J.C.) and NIH grant P30 CA125123 (C.J.C.). R.M. was supported by the Ruth L. Kirschstein National Research Service Award Individual Pre-doctoral Fellowship to Promote Diversity in Health-Related Research (NCI F31 CA232403-01) and Dr. John J. Kopchick Fellowship. D.P. was supported by a CPRIT Graduate Scholar Training Grant (RP140106). D.L.G. is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F Shelby Scholarship Fund. Work in the BR lab was supported by the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. We would like to thank Dr. Andrew Gladden for providing critical feedback and reagents, Laura Gibson for technical assistance and the UTMDACC Department of Veterinary Medicine Facility. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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doi = "10.1038/s41467-019-12832-z",

language = "English (US)",

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journal = "Nature communications",

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T1 - ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and promote metastasis in lung cancer

AU - Manshouri, Roxsan

AU - Coyaud, Etienne

AU - Kundu, Samrat T.

AU - Peng, David H.

AU - Stratton, Sabrina A.

AU - Alton, Kendra

AU - Bajaj, Rakhee

AU - Fradette, Jared J.

AU - Minelli, Rosalba

AU - Peoples, Michael D.

AU - Carugo, Alessandro

AU - Chen, Fengju

AU - Bristow, Christopher

AU - Kovacs, Jeffrey J.

AU - Barton, Michelle C.

AU - Heffernan, Tim

AU - Creighton, Chad J.

AU - Raught, Brian

AU - Gibbons, Don L.

N1 - Funding Information: This work was supported by the NIH R37 CA214609-01A1, CPRIT-MIRA RP160652-P3, and Rexanna’s Foundation for Fighting Lung Cancer to D.L.G., CPRIT multi-investigator award RP120713 C2 (C.J.C.) and NIH grant P30 CA125123 (C.J.C.). R.M. was supported by the Ruth L. Kirschstein National Research Service Award Individual Pre-doctoral Fellowship to Promote Diversity in Health-Related Research (NCI F31 CA232403-01) and Dr. John J. Kopchick Fellowship. D.P. was supported by a CPRIT Graduate Scholar Training Grant (RP140106). D.L.G. is an R. Lee Clark Fellow of the University of Texas MD Anderson Cancer Center, supported by the Jeane F Shelby Scholarship Fund. Work in the BR lab was supported by the Canada Foundation for Innovation and The Princess Margaret Cancer Foundation. The work was also supported by the generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shots Program. We would like to thank Dr. Andrew Gladden for providing critical feedback and reagents, Laura Gibson for technical assistance and the UTMDACC Department of Veterinary Medicine Facility. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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JO - Nature communications

JF - Nature communications

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M1 - 5125

ER -

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

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