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.
Proteasome inhibitors: new class of antitumor agents