The ubiquitin ligase RNF8 regulates Rho GTPases and promotes cytoskeletal changes and motility in triple-negative breast cancer cells

FEBS Lett. 2021 Jan;595(2):241-252. doi: 10.1002/1873-3468.13999. Epub 2020 Dec 5.

Abstract

The ubiquitin ligase RNF8 is known to induce epithelial-to-mesenchymal (EMT) transition and metastasis in triple-negative breast cancer (TNBC). Besides EMT, Rho GTPases have been shown as key regulators in metastasis. In this study, we investigated the role of RNF8 in regulating Rho GTPases and cell motility. We find that RNF8 knockdown in TNBC cells attenuates the protein and mRNA levels of Ras homolog family member A (RHOA) and cell division cycle 42 (CDC42). We show that the formation of filopodia, focal adhesions, and the association of focal adhesions to stress fibers is impaired upon RNF8 knockdown. Cell migration is significantly inhibited by RNF8 knockdown. Our study suggests a potential novel role for RNF8 in mediating cell migration in TNBC through regulation of the Rho GTPases RHOA and CDC42.

Keywords: CDC42; RHOA; RNF8; cell migration; cytoskeleton rearrangements; filopodia; focal adhesion; triple-negative breast cancer.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Focal Adhesions / metabolism
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Proteolysis
  • Pseudopodia / metabolism
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • cdc42 GTP-Binding Protein / genetics*
  • cdc42 GTP-Binding Protein / metabolism
  • rhoA GTP-Binding Protein / genetics*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • DNA-Binding Proteins
  • RNF8 protein, human
  • RHOA protein, human
  • Ubiquitin-Protein Ligases
  • CDC42 protein, human
  • cdc42 GTP-Binding Protein
  • rhoA GTP-Binding Protein