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Ubiquitin ligases in oncogenic transformation and cancer therapy

Nature Reviews Cancer volume 18, pages 69–88 (2018)Cite this article

Subjects

Key Points

  • Ubiquitin ligases (E3s) are deregulated in cancer through diverse mechanisms, resulting in altered expression and/or activity of their target proteins.

  • Deregulated E3s contribute to uncontrolled proliferation and genomic instability that drive malignant transformation, tumour progression and therapy resistance.

  • E3s regulate major growth-promoting pathways, including those targeted by current anticancer therapies such as the MAPK or PI3K–AKT–mTOR pathways.

  • By modulating the cellular response to stress, E3s orchestrate a balance between cell growth and survival signals, which control tumour initiation and progression.

  • Cancer-associated E3s affect transcription by modulating the abundance and activity of transcriptional activators, the binding of transcriptional activators to DNA and the formation of transcriptional complexes at genes and by regulating chromatin structure.

  • E3s are important regulators of mitochondrial and receptor-mediated apoptotic and necroptotic pathways; deregulation of these pathways confers a survival advantage to cancer cells.

  • Targeting E3s is one of the more challenging areas in drug development. Increasing our understanding of their structures (that is, their crystal structures) on their own or as part of E3 complexes and of the modifications that regulate the spatial and temporal activity of E3s is expected to guide the development of biologics and small-molecule inhibitors for this class of proteins.

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.

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Figure 1: Mechanisms underlying deregulated ubiquitylation in cancer.
Figure 2: Cellular processes affected by deregulated ubiquitylation in cancer.
Figure 3: Ubiquitin ligases coordinate the cell cycle and DNA damage repair to maintain genome integrity.
Figure 4: Regulation of mitotic signalling by ubiquitin ligases.
Figure 5: Ubiquitin ligases regulate the intrinsic and extrinsic apoptotic pathways.

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Acknowledgements

The authors are supported by US National Cancer Institute (NCI) grants CA207118 (to J.Q.) and CA128814 and CA111515 (to Z.A.R.), by the US Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program Award W81XWH-14-1-0551 (to Z.A.R.) and by a V Foundation Scholar Award V2016-026 (to J.Q.). The opinions, interpretations, conclusions and recommendations stated here are those of the authors and are not necessarily endorsed by the US Department of Defense.

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Authors and Affiliations

  1. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, 92130, California, USA

    Daniela Senft & Ze'ev A. Ronai

  2. University of Maryland School of Medicine, Baltimore, 21201, Maryland, USA

    Jianfei Qi

  3. Technion Integrated Cancer Center, Technion, Israel Institute of Technology Faculty of Medicine, Haifa, 31096, Israel

    Ze'ev A. Ronai

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  1. Daniela Senft
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Contributions

D.S. and J.Q. researched the data for the article. Z.A.R. provided a substantial contribution to discussions of the content. D.S. and Z.A.R. contributed equally to writing the article and to reviewing and/or editing the manuscript before submission.

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Correspondence to Ze'ev A. Ronai.

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Supplementary information

Supplementary information S1 (table)

Examples of deregulated E3 ubiquitin ligases in cancer (DOC 1585 kb)

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Glossary

Ubiquitylation

An enzymatic reaction that leads to the attachment of ubiquitin moieties either to ubiquitin itself (creating polyubiquitin chains) or to other proteins via isopeptide linkages.

Ubiquitin-activating enzymes

(E1s). Enzymes that activate ubiquitin in an ATP-dependent manner.

Ubiquitin-conjugating enzymes

(E2s). Enzymes that first accept activated ubiquitin from a ubiquitin-activating enzyme (E1) and then transfer it to substrates.

Ubiquitin ligases

(E3s). Enzymes that facilitate substrate recognition and guide the transfer of activated ubiquitin from the ubiquitin-conjugating enzyme (E2) to specific substrates.

Mitophagy

The selective autophagic clearance of damaged mitochondria.

Cyclins

A family of regulatory proteins that show oscillating expression throughout the cell cycle and that are required for the activation of cyclin-dependent kinases.

Cyclin-dependent kinase

(CDK). A type of protein that belongs to a group of serine and threonine kinases that require cyclins for activation and regulate cell cycle progression.

Haploinsufficient

A state in which one copy of a gene is inactivated or deleted and the remaining functional copy is not sufficient to preserve normal function.

Replication origins

Sites in the DNA where the replication machinery is loaded at the onset of DNA synthesis.

Spindle assembly checkpoint

(SAC). A stage in the cell cycle that is activated during mitosis and meiosis to delay cell division until all chromosomes are correctly attached to the spindle.

Phosphodegron

One or multiple phosphorylated residues in a protein substrate that are necessary for recognition by some ubiquitin ligases.

Destruction box

(D-box). A conserved sequence of amino acids (RxxL) in proteins that is recognized by the APC/C (anaphase-promoting complex; also known as the cyclosome).

Micronuclei

Extranuclear bodies that form if chromosome fragments or entire chromosomes are not incorporated into the nucleus following cell division.

Non-homologous end joining

(NHEJ). An error-prone mechanism to repair DNA double strand breaks whereby the broken ends can be ligated, even with little or no sequence complementarity.

Base excision repair

(BER). A DNA repair mechanism that replaces bases that are damaged as a result of oxidation, deamination or alkylation.

Deubiquitylating enzyme

(DUB). A protease (cysteine protease or metalloproteinase) that cleaves the isopeptide linkage between the protein substrate (which can be ubiquitin itself) and the ubiquitin residue.

Hypoxic tension

The level of oxygen (usually measured as a percentage) in a given tissue or microenvironment. The lower the level of oxygen, the higher the tension.

Unfolded protein response

(UPR). A well-defined process that plays a critical role in restoring homeostasis following accumulation of potentially toxic misfolded proteins in the endoplasmic reticulum.

Succination

A process wherein fumarate reacts with cysteine residues in proteins by a Michael addition reaction to form S-(2-succinyl) cysteine.

Mitochondrial depolarization

The change in the resting potential (negative membrane potential) of mitochondria in the depolarizing direction (positive membrane potential), which is a critical step in the induction of mitochondrial apoptosis.

Degrons

Specific sequences of amino acids in a substrate that are necessary for recognition by the ubiquitin ligase.

Linear ubiquitin chain assembly complex

(LUBAC). An atypical ubiquitin ligase complex that consists of haeme-oxidized IRP2 ubiquitin ligase 1 (HOIL1; also known as RBCK1), HOIL1-interacting protein (HOIP; also known as RNF31) and the non-catalytic subunit shank-associated RH domain-interacting protein (SHARPIN). The LUBAC mediates M1-linked polyubiquitylation of its substrates and regulates, among other processes, nuclear factor-κB (NF-κB) and MAPK activation downstream of tumour necrosis factor receptor (TNFR) signalling.

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Senft, D., Qi, J. & Ronai, Z. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer 18, 69–88 (2018). https://doi.org/10.1038/nrc.2017.105

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