1. ¹IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy
2. ²Istituto Europeo di Oncologia, Milan, Italy
3. ³Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita' degli Studi di Milano, Milan, Italy

Correspondence: Dr S Confalonieri, IFOM Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, Milan 20139, Italy. E-mails: stefano.confalonieri@ifom-ieo-campus.it; Professor PP Di Fiore, pierpaolo.difiore@ifom-ieo-campus.it

Received 15 October 2008; Revised 13 April 2009; Accepted 11 May 2009; Published online 22 June 2009.

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.