The stability and oncogenic function of LIN28A are regulated by USP28

Biochim Biophys Acta Mol Basis Dis. 2019 Mar 1;1865(3):599-610. doi: 10.1016/j.bbadis.2018.12.006. Epub 2018 Dec 10.

Abstract

RNA-binding protein LIN28A is often highly expressed in human malignant tumors and is involved in tumor metastasis and poor prognosis. Knowledge about post-translational regulatory mechanisms governing LIN28A protein stability and function is scarce. Here, we investigated the role of ubiquitination and deubiquitination on LIN28A protein stability and report that LIN28A protein undergoes ubiquitination. Ubiquitin-specific protease 28 (USP28), a deubiquitinating enzyme, interacts with and stabilizes LIN28A protein to extend its half-life. USP28, through its deubiquitinating activity, antagonizes LIN28A protein turnover by reversing its proteasomal degradation. Our study describes the consequential impacts of USP28-mediated stabilization of LIN28A protein on enhancing cancer cell viability, migration and ultimately augmenting LIN28A-mediated tumor progression. Overall, our data suggest that a synergistic, combinatorial approach of targeting LIN28A with USP28 would contribute to effective cancer therapeutics.

Keywords: CRISPR/Cas9; Cell viability; Knockout cell lines; Let-7; Protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / genetics*
  • Cells, Cultured
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • HeLa Cells
  • Humans
  • K562 Cells
  • MCF-7 Cells
  • Oncogenes / physiology
  • Protein Binding
  • Protein Processing, Post-Translational / genetics
  • Protein Stability
  • Proteolysis
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • RNA-Binding Proteins / physiology*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / physiology*
  • Ubiquitination

Substances

  • LIN28B protein, human
  • RNA-Binding Proteins
  • USP28 protein, human
  • Ubiquitin Thiolesterase