A portrayal of E3 ubiquitin ligases and deubiquitylases in cancer

Int J Cancer. 2013 Dec 15;133(12):2759-68. doi: 10.1002/ijc.28129. Epub 2013 Mar 25.


E3 ubiquitin ligases and deubiquitylating enzymes (DUBs) are the key components of ubiquitin proteasome system which plays a critical role in cellular protein homeostasis. Any shortcoming in their biological roles can lead to various diseases including cancer. The dynamic interplay between ubiquitylation and deubiquitylation determines the level and activity of several proteins including p53, which is crucial for cellular stress response and tumor suppression pathways. In this review, we describe the different types of E3 ubiquitin ligases including those targeting tumor suppressor p53, SCF ligases and RING type ligases and accentuate on biological functions of few important E3 ligases in the cellular regulatory networks. Tumor suppressor p53 level is tightly regulated by multiple E3 ligases including Mdm2, COP1, Pirh2, etc. SCF ubiquitin ligase complexes are key regulators of cell cycle and signal transduction. BRCA1 and VHL RING type ligases function as tumor suppressors and play an important role in DNA repair and hypoxia response respectively. Further, we discuss the biological consequences of deregulation of the E3 ligases and the implications for cancer development. We also describe deubiquitylases which reverse the process of ubiquitylation and regulate diverse cellular pathways including metabolism, cell cycle control and chromatin remodelling. As the E3 ubiquitin ligases and DUBs work in a substrate specific manner, an improved understanding of them can lead to better therapeutics for cancer.

Keywords: cancer; p53; proteasome; ubiquitylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • BRCA1 Protein / physiology
  • Humans
  • Neoplasms / etiology*
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins c-mdm2 / physiology
  • Thiolester Hydrolases / physiology
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin / metabolism*
  • Ubiquitin Thiolesterase / physiology
  • Ubiquitin-Protein Ligases / physiology*
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination


  • BRCA1 Protein
  • Tumor Suppressor Protein p53
  • USP10 protein, human
  • Ubiquitin
  • Proto-Oncogene Proteins c-mdm2
  • RCHY1 protein, human
  • Ubiquitin-Protein Ligases
  • Thiolester Hydrolases
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7
  • Usp22 protein, human