SnoRNA U50 is a candidate tumor-suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer

Abstract

Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor-suppressor genes in 6q. To identify the 6q tumor-suppressor gene, we first narrowed the common region of deletion to a 2.5 Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2 bp (TT) deletion, was found in two of 30 prostate cancer cell lines/xenografts and nine of 89 localized prostate cancers (eleven of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio 2.9; 95% confidence interval 1.17-7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor-suppressor gene in prostate cancer and likely in other types of cancers.

GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer

“…Recent genetic and functional analyses have indicated that the snoRNA U50 is a candidate tumor suppressor (Dong et al, 2008). U50 is found at a chromosome breakpoint in a human B-cell lymphoma (Tanaka et al, 2000) and, like GAS5, is a member of the 5 0 TOP gene family encoding box C/D snoRNAs within the introns of a gene with no significant protein-coding potential (Tanaka et al, 2000).…”

“…We also show that GAS5 expression is significantly downregulated in breast cancer cells, suggesting that a decrease in expression levels may be significant in oncogenesis. The recent observations that the GAS5 gene becomes fused to the BCL6 gene in a B-cell lymphoma (Nakamura et al, 2008) and that mutation in the related snoRNA U50 is associated with clinically significant prostate cancer (Dong et al, 2008) indicate that these non-protein-coding snoRNAs play a widespread but previously unsuspected role in the development and therapy of cancer.…”

Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer

“…In PCa, snoRNA U50 has been reported to be a candidate tumor-suppressor gene and a mutation in its sequence has been associated with clinically significant disease (Dong et al, 2008). Recent findings have demonstrated that discrete in size snoRNA fragments are produced from a vast majority of snoRNA loci (Taft et al, 2009) and that they can also function as miRNAs The small transcriptome of prostate cancer ES Martens-Uzunova et al (Ender et al, 2008;Brameier et al, 2011).…”

“…Several microRNAs (miRNAs) are now associated with the progression and classification of this and other malignancies (Lu et al, 2005;Volinia et al, 2006;Porkka et al, 2007;Shi et al, 2007;Ozen et al, 2008;Prueitt et al, 2008;Tong et al, 2009). Evidence is accumulating that small nuclear RNA and small nucleolar RNA (snoRNA) are also employed in cis and trans gene regulation and alternative splicing besides their established function in ribosomal RNA modification (Reis et al, 2004;Mattick and Makunin, 2006;Dong et al, 2008;Ender et al, 2008). Nevertheless, the assessment of the complete small ncRNA transcriptome involved in the formation and differentiation of different types and subtypes of PCa has remained a challenge.…”

Les petits ARN nucléolaires nous surprennent encore !

“…REVUES à indiquer que plusieurs snoARN sont également impliqués dans des processus tumoraux [27][28][29][30][31]. Par exemple, le snoARN à boîtes C/D U50 est sous-exprimé chez certains patients atteints de cancer de la prostate, et sa surexpression inhibe la prolifération cellulaire in vitro [32][33][34]. Un autre snoARN, à boîte H/ACA cette fois, est surexprimé dans certains types de cancers du poumon [25,35].…”