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Nat Rev Cancer. 2018 Feb;18(2):69-88. doi: 10.1038/nrc.2017.105. Epub 2017 Dec 15.

Ubiquitin ligases in oncogenic transformation and cancer therapy.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92130, USA.
2
University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
3
Technion Integrated Cancer Center, Technion, Israel Institute of Technology Faculty of Medicine, Haifa 31096, Israel.

Abstract

The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

PMID:
29242641
PMCID:
PMC6054770
DOI:
10.1038/nrc.2017.105
[Indexed for MEDLINE]
Free PMC Article

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