The Ubiquitin-Proteasome Pathway and Epigenetic Modifications in Cancer

Anticancer Agents Med Chem. 2021;21(1):20-32. doi: 10.2174/1871520620666200811114159.


Background: The ubiquitin-proteasome pathway is involved in almost all cellular processes (cell cycle, gene transcription and translation, cell survival and apoptosis, cell metabolism and protein quality control) mainly through the specific degradation of the majority of intracellular proteins (>80%) or partial processing of transcription factors (e.g., NF-κB). A growing amount of evidence now indicates that epigenetic changes are also regulated by the ubiquitin-proteasome pathway. Recent studies indicate that epigenetic regulations are equally crucial for almost all biological processes as well as for pathological conditions such as tumorigenesis, as compared to non-epigenetic control mechanisms (i.e., genetic alterations or classical signal transduction pathways).

Objective: Here, we reviewed the recent work highlighting the interaction of the ubiquitin-proteasome pathway components (e.g., ubiquitin, E1, E2 and E3 enzymes and 26S proteasome) with epigenetic regulators (histone deacetylases, histone acetyltransferases and DNA methyltransferases).

Results: Alterations in the regulation of the ubiquitin-proteasome pathway have been discovered in many pathological conditions. For example, a 2- to 32-fold increase in proteasomal activity and/or subunits has been noted in primary breast cancer cells. Although proteasome inhibitors have been successfully applied in the treatment of hematological malignancies (e.g., multiple myeloma), the clinical efficacy of the proteasomal inhibition is limited in solid cancers. Interestingly, recent studies show that the ubiquitin-proteasome and epigenetic pathways intersect in a number of ways through the regulation of epigenetic marks (i.e., acetylation, methylation and ubiquitylation).

Conclusion: It is therefore believed that novel treatment strategies involving new generation ubiquitinproteasome pathway inhibitors combined with DNA methyltransferase, histone deacetylase or histone acetyltransferase inhibitors may produce more effective results with fewer adverse effects in cancer treatment as compared to standard chemotherapeutics in hematological as well as solid cancers.

Keywords: Bortezomib; cancer; epigenetics; histone deacetylase; proteasome; ubiquitin.

Publication types

  • Review

MeSH terms

  • Acetylation
  • Boron Compounds / pharmacology
  • Bortezomib / chemistry
  • Bortezomib / pharmacology
  • DNA Modification Methylases / antagonists & inhibitors
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epigenesis, Genetic / drug effects*
  • Glycine / analogs & derivatives
  • Glycine / pharmacology
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Methylation
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemistry*
  • Proteasome Inhibitors / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Processing, Post-Translational / drug effects*
  • Signal Transduction
  • Terphenyl Compounds / pharmacology
  • Ubiquitin / metabolism*
  • Ubiquitination
  • Valproic Acid / pharmacology


  • Boron Compounds
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • NF-kappa B
  • Proteasome Inhibitors
  • Terphenyl Compounds
  • Ubiquitin
  • WT161
  • Valproic Acid
  • Bortezomib
  • ixazomib
  • DNA Modification Methylases
  • Histone Acetyltransferases
  • Proteasome Endopeptidase Complex
  • Histone Deacetylases
  • Glycine