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Alterations of ubiquitin ligases in human cancer and their association with the natural history of the tumor

Oncogene volume 28, pages 2959–2968 (2009)Cite this article

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

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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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Authors and Affiliations

  1. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

    S Confalonieri, M Quarto, P Nuciforo, G Jodice, S Pece & P P Di Fiore

  2. Istituto Europeo di Oncologia, Milan, Italy

    G Goisis, M Donzelli, G Pelosi, G Viale, S Pece & P P Di Fiore

  3. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, Milan, Italy

    G Pelosi, G Viale, S Pece & P P Di Fiore

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  1. S Confalonieri
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Correspondence to S Confalonieri or P P Di Fiore.

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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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