Abstract
Clear cell renal cell carcinoma (ccRCC) is intimately associated with defects in ubiquitin-mediated protein degradation. Herein, we report that deficiency in the E3 ligase subunit cullin 5 (CUL5) promotes chromosomal instability and is an independent negative prognostic factor in ccRCC. CUL5 was initially identified in an RNA interference screen as a novel regulator of centrosome duplication control. We found that depletion of CUL5 rapidly promotes centriole overduplication and mitotic errors. Downregulation of CUL5 also caused an increase of DNA damage that was found to involve impaired DNA double-strand break repair. Using immunohistochemistry, CUL5 protein expression was found to be below detection level in the majority of RCCs. A re-analysis of the TCGA ccRCC cohort showed that a reduced CUL5 gene expression or CUL5 deletion were associated with a significantly worse overall patient survival. In conclusion, our results indicate that CUL5 functions as a novel tumor suppressor with prognostic relevance in ccRCC and is critically involved in the maintenance of genome stability.
Highlights
Kidney cancer affects over 300,000 people worldwide annually and is one of the most lethal urological malignancies once metastatic[1]
Downregulation of cullin 5 (CUL5) promotes centriole overduplication To explore the role of cullins in the maintenance of mitotic fidelity, we performed a small interfering RNA mini-screen of seven human cullin subunits
Knock-down of CUL5 produces a genuine centriole duplication defect When we performed an immunofluorescence microscopic analysis of U-2 OS/centrin-GFP cells for γ-tubulin after depletion of CUL5 by small interfering RNA (siRNA), we found a sixfold increase in the number of γ-tubulin dots per cell underscoring that supernumerary centrioles induced by knock-down of CUL5 undergo maturation and can potentially function as microtubuleorganizing centers in cells
Summary
Kidney cancer affects over 300,000 people worldwide annually and is one of the most lethal urological malignancies once metastatic[1]. CcRCC is characterized by chromosomal instability including numerical and structural chromosomal alterations[3]. Some of these alterations such as the loss of chromosome 3p are highly ccRCC, which, together with structural changes and single-nucleotide variants[7] contribute to the extensive intratumoral genetic heterogeneity characteristic of ccRCC8,9. Numerical and structural chromosomal aberrations are caused by mitotic defects and errors in DNA damage repair, respectively, which frequently coincide in cancer cells[10]. In ccRCC, the inactivation of the VHL tumor suppressor gene, which occurs in the large majority of patients, has been shown to lead to defective mitoses and to interfere with DNA double-strand break (DSB) repair[11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
