The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer.

Abstract

Small nucleolar RNAs (snoRNAs) are conserved noncoding RNAs best studied as ribonucleoprotein (RNP) guides in RNA modification. To explore their role in cancer, we compared 5,473 tumor-normal genome pairs to identify snoRNAs with frequent copy number loss. The SNORD50A-SNORD50B snoRNA locus was deleted in 10-40% of 12 common cancers, where its loss was associated with reduced survival. A human protein microarray screen identified direct SNORD50A and SNORD50B RNA binding to K-Ras. Loss of SNORD50A and SNORD50B increased the amount of GTP-bound, active K-Ras and hyperactivated Ras-ERK1/ERK2 signaling. Loss of these snoRNAs also increased binding by farnesyltransferase to K-Ras and increased K-Ras prenylation, suggesting that KRAS mutation might synergize with SNORD50A and SNORD50B loss in cancer. In agreement with this hypothesis, CRISPR-mediated deletion of SNORD50A and SNORD50B in KRAS-mutant tumor cells enhanced tumorigenesis, and SNORD50A and SNORD50B deletion and oncogenic KRAS mutation co-occurred significantly in multiple human tumor types. SNORD50A and SNORD50B snoRNAs thus directly bind and inhibit K-Ras and are recurrently deleted in human cancer.

• Authors: Zurab Siprashvili, Dan E Webster, Danielle Johnston, Rajani M Shenoy, Alexander J Ungewickell, Aparna Bhaduri, Ross Flockhart, Brian J Zarnegar, Yonglu Che, Francesca Meschi, Joseph D Puglisi, Paul A Khavari
• Journal: Nature genetics (Nat Genet) Vol. 48 Issue 1 Pg. 53-8 (Jan 2016) ISSN: 1546-1718 [Electronic] United States
• PMID: 26595770 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Small Nucleolar
• RNA, Untranslated
• Guanosine Triphosphate
• ras Proteins

Topics

• Animals
• Cell Line, Tumor
• Clustered Regularly Interspaced Short Palindromic Repeats
• Female
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Guanosine Triphosphate (metabolism)
• Humans
• Mice, Inbred NOD
• Mutation
• Neoplasms (genetics, mortality)
• Prenylation
• RNA, Small Nucleolar (genetics, metabolism)
• RNA, Untranslated (genetics, metabolism)
• Xenograft Model Antitumor Assays
• ras Proteins (genetics, metabolism)