Ubiquitin Ligases in Cancer: Functions and Clinical Potentials

Overview

Journal Cell Chem Biol

Publisher Cell Press

Specialty Biochemistry

Date 2021 May 11

PMID 33974914

Citations 23

Authors

Shanshan Duan

Michele Pagano

Affiliations

Soon will be listed here.

Abstract

Ubiquitylation, a highly regulated post-translational modification, controls many cellular pathways that are critical to cell homeostasis. Ubiquitin ligases recruit substrates and promote ubiquitin transfer onto targets, inducing proteasomal degradation or non-degradative signaling. Accumulating evidence highlights the critical role of dysregulated ubiquitin ligases in processes associated with the initiation and progression of cancer. Depending on the substrate specificity and biological context, a ubiquitin ligase can act either as a tumor promoter or as a tumor suppressor. In this review, we focus on the regulatory roles of ubiquitin ligases and how perturbations of their functions contribute to cancer pathogenesis. We also briefly discuss current strategies for targeting or exploiting ubiquitin ligases for cancer therapy.

Citing Articles

A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins.

Ganesan I, Kiyokawa H Cancers (Basel). 2025; 17(4).

PMID: 40002221 PMC: 11853300. DOI: 10.3390/cancers17040626.

Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities.

Awan A, Osman M, Khan O Cells. 2025; 14(2).

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The RING Finger E3 Ligase RNF25 Protects DNA Replication Forks Independently of its Canonical Roles in Ubiquitin Signaling.

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Filis P, Peschos D, Simos Y, Filis N, Zachariou C, Stagikas D Ann Gastroenterol. 2025; 38(1):85-92.

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DCAF15 control of cohesin dynamics sustains acute myeloid leukemia.

Grothusen G, Chang R, Cao Z, Zhou N, Mittal M, Datta A Nat Commun. 2024; 15(1):5604.

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References

Motta M, Fidan M, Bellacchio E, Pantaleoni F, Schneider-Heieck K, Coppola S . Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Hum Mol Genet. 2018; 28(6):1007-1022. DOI: 10.1093/hmg/ddy412. View

Chao J, Parganas E, Boyd K, Hong C, Opferman J, Ihle J . Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature. 2008; 452(7183):98-102. DOI: 10.1038/nature06604. View

Sullivan C, Pipas J . T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis. Microbiol Mol Biol Rev. 2002; 66(2):179-202. PMC: 120785. DOI: 10.1128/MMBR.66.2.179-202.2002. View

Koh M, Powis G . Passing the baton: the HIF switch. Trends Biochem Sci. 2012; 37(9):364-72. PMC: 3433036. DOI: 10.1016/j.tibs.2012.06.004. View

Manfredi J . The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev. 2010; 24(15):1580-9. PMC: 2912554. DOI: 10.1101/gad.1941710. View

Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K . Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes Dev. 2008; 22(8):986-91. PMC: 2335330. DOI: 10.1101/gad.1621808. View

Maxwell P, Wiesener M, Chang G, Clifford S, Vaux E, Cockman M . The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399(6733):271-5. DOI: 10.1038/20459. View

Thomas M, Banks L . Inhibition of Bak-induced apoptosis by HPV-18 E6. Oncogene. 1999; 17(23):2943-54. DOI: 10.1038/sj.onc.1202223. View

Katsir L, Schilmiller A, Staswick P, He S, Howe G . COI1 is a critical component of a receptor for jasmonate and the bacterial virulence factor coronatine. Proc Natl Acad Sci U S A. 2008; 105(19):7100-5. PMC: 2383947. DOI: 10.1073/pnas.0802332105. View

10.

Bigenzahn J, Collu G, Kartnig F, Pieraks M, Vladimer G, Heinz L . LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018; 362(6419):1171-1177. PMC: 6794158. DOI: 10.1126/science.aap8210. View

11.

Romero R, Sayin V, Davidson S, Bauer M, Singh S, LeBoeuf S . Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat Med. 2017; 23(11):1362-1368. PMC: 5677540. DOI: 10.1038/nm.4407. View

12.

Pavlova N, Thompson C . The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016; 23(1):27-47. PMC: 4715268. DOI: 10.1016/j.cmet.2015.12.006. View

13.

Sheard L, Tan X, Mao H, Withers J, Ben-Nissan G, Hinds T . Jasmonate perception by inositol-phosphate-potentiated COI1-JAZ co-receptor. Nature. 2010; 468(7322):400-5. PMC: 2988090. DOI: 10.1038/nature09430. View

14.

Welcker M, Clurman B . The SV40 large T antigen contains a decoy phosphodegron that mediates its interactions with Fbw7/hCdc4. J Biol Chem. 2004; 280(9):7654-8. DOI: 10.1074/jbc.M413377200. View

15.

Potente M, Gerhardt H, Carmeliet P . Basic and therapeutic aspects of angiogenesis. Cell. 2011; 146(6):873-87. DOI: 10.1016/j.cell.2011.08.039. View

16.

King R, Deshaies R, Peters J, Kirschner M . How proteolysis drives the cell cycle. Science. 1996; 274(5293):1652-9. DOI: 10.1126/science.274.5293.1652. View

17.

Fischer E, Bohm K, Lydeard J, Yang H, Stadler M, Cavadini S . Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature. 2014; 512(7512):49-53. PMC: 4423819. DOI: 10.1038/nature13527. View

18.

Dehan E, Bassermann F, Guardavaccaro D, Vasiliver-Shamis G, Cohen M, Lowes K . betaTrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis. Mol Cell. 2009; 33(1):109-16. PMC: 2655121. DOI: 10.1016/j.molcel.2008.12.020. View

19.

Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M . Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993; 260(5112):1338-43. DOI: 10.1126/science.8493579. View

20.

Vucic D, Stennicke H, Pisabarro M, Salvesen G, Dixit V . ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol. 2000; 10(21):1359-66. DOI: 10.1016/s0960-9822(00)00781-8. View