A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells

Lucy Ginn, Joe Maltas, Martin j. Baker, Anshuman Chaturvedi, Leah Wilson, Ryan Guilbert, Fabio m. r. Amaral, Lynsey Priest, Holly Mole, Fiona Blackhall, Zoi Diamantopoulou, Tim c. p. Somervaille, Adam Hurlstone, Angeliki Malliri

Research output: Contribution to journalArticlepeer-review

Abstract

Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell–cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.
Original languageEnglish
Article numbere2300489120
JournalProceedings of the National Academy of Sciences
Volume120
Issue number40
Early online date25 Sept 2023
DOIs
Publication statusPublished - 3 Oct 2023

Keywords

  • TIAM1
  • RAC
  • migration
  • NSCLC
  • EMT

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