Abstract
Protein ubiquitination is critical for many cellular processes, through its ability to regulate protein degradation and various signaling mechanisms. In the ubiquitin (Ub) system, substrate specificity is achieved through the E3 family of Ub ligases. Because alterations of the ubiquitination machinery have been reported in human cancers, the selective interference with Ub ligases might represent a powerful therapeutic tool. Here, we report the first wide survey of misregulation of Ub ligases in cancer. We analysed 82 Ub ligases in nine types of cancer by in situ hybridization on tissue microarrays. We found 27 instances in which an Ub ligase was altered in a given type of tumor, when compared with normal tissues: 21 cases of overexpression and 6 cases of underexpression. We further analysed selected Ub ligases in large cohorts of breast and non-small-cell lung carcinomas. In five, of six, of these extended analyses (HUWE1, CCNB1IP1, SIAH1 and SIAH2 in breast cancer and CCNB1IP1 in lung cancer), we found that the levels of Ub ligases correlated significantly with relevant prognostic factors, and with clinical outcome. Our findings show that the alteration of Ub ligases is a frequent event in cancer and identify candidate targets for molecular therapies.
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Abbreviations
- Ub:
-
ubiquitin
- ISH:
-
in situ hybridization
- TMA:
-
tissue microarray
References
Adhikary S, Marinoni F, Hock A, Hulleman E, Popov N, Beier R et al. (2005). The ubiquitin ligase HectH9 regulates transcriptional activation by Myc and is essential for tumor cell proliferation. Cell 123: 409–421.
Bernassola F, Karin M, Ciechanover A, Melino G . (2008). The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 14: 10–21.
Borlado LR, Mendez J . (2008). CDC6: from DNA replication to cell cycle checkpoints and oncogenesis. Carcinogenesis 29: 237–243.
Buchwald G, van der Stoop P, Weichenrieder O, Perrakis A, van Lohuizen M, Sixma TK . (2006). Structure and E3-ligase activity of the Ring–Ring complex of polycomb proteins Bmi1 and Ring1b. EMBO J 25: 2465–2474.
Capra M, Nuciforo PG, Confalonieri S, Quarto M, Bianchi M, Nebuloni M et al. (2006). Frequent alterations in the expression of serine/threonine kinases in human cancers. Cancer Res 66: 8147–8154.
Chen D, Kon N, Li M, Zhang W, Qin J, Gu W . (2005). ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell 121: 1071–1083.
Ciechanover A . (2003). The ubiquitin proteolytic system and pathogenesis of human diseases: a novel platform for mechanism-based drug targeting. Biochem Soc Trans 31: 474–481.
Ciechanover A, Schwartz AL . (2002). Ubiquitin-mediated degradation of cellular proteins in health and disease. Hepatology 35: 3–6.
Dong Y, Sui L, Watanabe Y, Sugimoto K, Tokuda M . (2002). Clinical relevance of cyclin B1 overexpression in laryngeal squamous cell carcinoma. Cancer Lett 177: 13–19.
Fiucci G, Beaucourt S, Duflaut D, Lespagnol A, Stumptner-Cuvelette P, Geant A et al. (2004). Siah-1b is a direct transcriptional target of p53: identification of the functional p53 responsive element in the siah-1b promoter. Proc Natl Acad Sci USA 101: 3510–3515.
Gautreau A, Manent J, Fievet B, Louvard D, Giovannini M, Arpin M . (2002). Mutant products of the NF2 tumor suppressor gene are degraded by the ubiquitin–proteasome pathway. J Biol Chem 277: 31279–31282.
Hall JR, Kow E, Nevis KR, Lu CK, Luce KS, Zhong Q et al. (2007). Cdc6 stability is regulated by the Huwe1 ubiquitin ligase after DNA damage. Mol Biol Cell 18: 3340–3350.
Hassan KA, Ang KK, El-Naggar AK, Story MD, Lee JI, Liu D et al. (2002). Cyclin B1 overexpression and resistance to radiotherapy in head and neck squamous cell carcinoma. Cancer Res 62: 6414–6417.
Hershko A, Ciechanover A . (1998). The ubiquitin system. Annu Rev Biochem 67: 425–479.
Hoppe T . (2005). Multiubiquitylation by E4 enzymes: ‘one size’ doesn't fit all. Trends Biochem Sci 30: 183–187.
Kallijarvi J, Lahtinen U, Hamalainen R, Lipsanen-Nyman M, Palvimo JJ, Lehesjoki AE . (2005). TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase. Exp Cell Res 308: 146–155.
Kim M, Tezuka T, Tanaka K, Yamamoto T . (2004). Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 23: 1645–1655.
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S et al. (1998). Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4: 844–847.
Lau E, Zhu C, Abraham RT, Jiang W . (2006). The functional role of Cdc6 in S–G2/M in mammalian cells. EMBO R 7: 425–430.
Liu J, Stevens J, Rote CA, Yost HJ, Hu Y, Neufeld KL et al. (2001). Siah-1 mediates a novel beta-catenin degradation pathway linking p53 to the adenomatous polyposis coli protein. Mol Cell 7: 927–936.
Lobrich M, Jeggo PA . (2007). The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer 7: 861–869.
Matsuzawa SI, Reed JC . (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell 7: 915–926.
Meroni G, Diez-Roux G . (2005). TRIM/RBCC, a novel class of ‘single protein RING finger’ E3 ubiquitin ligases. Bioessays 27: 1147–1157.
Mukhopadhyay D, Riezman H . (2007). Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science 315: 201–205.
Nakayama KI, Nakayama K . (2006). Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6: 369–381.
Nicassio F, Bianchi F, Capra M, Vecchi M, Confalonieri S, Bianchi M et al. (2005). A cancer-specific transcriptional signature in human neoplasia. J Clin Invest 115: 3015–3025.
Oehlmann M, Score AJ, Blow JJ . (2004). The role of Cdc6 in ensuring complete genome licensing and S phase checkpoint activation. J Cell Biol 165: 181–190.
Orlowski RZ, Kuhn DJ . (2008). Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14: 1649–1657.
Pelizon C . (2003). Down to the origin: Cdc6 protein and the competence to replicate. Trends Cell Biol 13: 110–113.
Scarafia LE, Winter A, Swinney DC . (2000). Quantitative expression analysis of the cellular specificity of HECT-domain ubiquitin E3 ligases. Physiol Genomics 4: 147–153.
Schauvliege R, Janssens S, Beyaert R . (2006). Pellino proteins are more than scaffold proteins in TLR/IL-1R signalling: a role as novel RING E3-ubiquitin-ligases. FEBS Lett 580: 4697–4702.
Sigismund S, Polo S, Di Fiore PP . (2004). Signaling through monoubiquitination. Curr Top Microbiol Immunol 286: 149–185.
Soria JC, Jang SJ, Khuri FR, Hassan K, Liu D, Hong WK et al. (2000). Overexpression of cyclin B1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res 60: 4000–4004.
Sun Y . (2006). E3 Ubiquitin ligases as cancer targets and biomarkers. Neoplasia 8: 645–654.
Toby GG, Gherraby W, Coleman TR, Golemis EA . (2003). A novel RING finger protein, human enhancer of invasion 10, alters mitotic progression through regulation of cyclin B levels. Mol Cell Biol 23: 2109–2122.
Vecchi M, Confalonieri S, Nuciforo P, Vigano MA, Capra M, Bianchi M et al. (2008). Breast cancer metastases are molecularly distinct from their primary tumors. Oncogene 27: 2148–2158.
Veronesi U, Paganelli G, Viale G, Luini A, Zurrida S, Galimberti V et al. (2003). A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349: 546–553.
Wang A, Yoshimi N, Ino N, Tanaka T, Mori H . (1997). Overexpression of cyclin B1 in human colorectal cancers. J Cancer Res Clin Oncol 123: 124–127.
Ward JO, Reinholdt LG, Motley WW, Niswander LM, Deacon DC, Griffin LB et al. (2007). Mutation in mouse hei10, an e3 ubiquitin ligase, disrupts meiotic crossing over. PLoS Genet 3: e139.
Weiss A, Baumgartner M, Radziwill G, Dennler J, Moelling K . (2007). c-Src is a PDZ interaction partner and substrate of the E3 ubiquitin ligase Ligand-of-Numb protein X1. FEBS Lett 581: 5131–5136.
Xia Y, Wang J, Xu S, Johnson GL, Hunter T, Lu Z . (2007). MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Mol Cell Biol 27: 510–517.
Yasuda M, Takesue F, Inutsuka S, Honda M, Nozoe T, Korenaga D . (2002). Overexpression of cyclin B1 in gastric cancer and its clinicopathological significance: an immunohistological study. J Cancer Res Clin Oncol 128: 412–416.
Yoon SY, Lee Y, Kim JH, Chung AS, Joo JH, Kim CN et al. (2005). Over-expression of human UREB1 in colorectal cancer: HECT domain of human UREB1 inhibits the activity of tumor suppressor p53 protein. Biochem Biophys Res Commun 326: 7–17.
Zhao X, Heng JI, Guardavaccaro D, Jiang R, Pagano M, Guillemot F et al. (2008). The HECT-domain ubiquitin ligase Huwe1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein. Nat Cell Biol 10: 643–653.
Zhong Q, Gao W, Du F, Wang X . (2005). Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 121: 1085–1095.
Acknowledgements
We thank Maria Capra and Maria Tuttoilmondo for TMA database development and TMA analysis, and Sara Volorio for excellent technical assistance. This work was supported by grants from AIRC (Associazione Italiana per la Ricerca sul Cancro) to SC, and from AIRC and MIUR to SP and PPDF; from the European Community (VI Framework), the Ferrari Foundation, the Monzino Foundation and the CARIPLO Foundation to PPDF; and from the G Vollaro Foundation to SP. PN was supported by an AIRC fellowship.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Confalonieri, S., Quarto, M., Goisis, G. et al. Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor. Oncogene 28, 2959–2968 (2009). https://doi.org/10.1038/onc.2009.156
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DOI: https://doi.org/10.1038/onc.2009.156
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