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

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.

Siah: A Promising Anticancer Target

“…In situ hybridization on cancer tissue microarrays revealed that gene expression of both SIAH1 and SIAH2 were downregulated in human breast cancer, correlating with decreased overall disease-free survival of patients (Table 1; ref. 23). This is in stark contrast with elevated Siah2 protein levels being associated with reduced survival and disease progression as discussed above (19,20), showing an apparent disconnect between the ability to predict outcomes solely based on Siah gene or protein abundance.…”

Mule/Huwe1/Arf-BP1 suppresses Ras-driven tumorigenesis by preventing c-Myc/Miz1-mediated down-regulation of p21 and p15

“…MULE is up-regulated in cancers of the breast, colon, lung, prostate, larynx, liver, pancreas, and thyroid but down-regulated in stomach and uterine tumors as well as glioblastomas (Adhikary et al 2005;Confalonieri et al 2009). The MULE locus is deleted in some glioblastoma patients (Zhao et al 2009) but commonly amplified in individuals with non-syndromic intellectual disability.…”

miR-195, miR-455-3p and miR-10a∗ are implicated in acquired temozolomide resistance in glioblastoma multiforme cells

“…Among these candidates, three genes (SIAH1, WEE1 and RANBP3), which are possible targets of miR-195, seem to be promising. SIAH1, an E3 ubiquitin ligase, was underexpressed in breast cancer compared to normal tissue, and low level of its expression correlated with decreased probability of disease-free survival [44]. SIAH1 is a p53 target gene and contributes to p53-mediated cell cycle arrest through -catenin pathway [45].…”