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

Nat Commun. 2019 Nov 12;10(1):5125. doi: 10.1038/s41467-019-12832-z.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Co-Repressor Proteins / metabolism
  • Endocytosis*
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
  • Mice
  • Models, Biological
  • Neoplasm Metastasis
  • Protein Binding
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Cadherins
  • Co-Repressor Proteins
  • GTPase-Activating Proteins
  • TBC1D2 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • rab GTP-Binding Proteins