title: 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.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Zurab
authors.initials: Z
authors.lastname: Siprashvili
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Webster
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Johnston
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Rajani M
authors.initials: RM
authors.lastname: Shenoy
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Ungewickell
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Bhaduri
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Flockhart
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Zarnegar
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Yonglu
authors.initials: Y
authors.lastname: Che
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Meschi
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Puglisi
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.|Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D016688:Mice, Inbred NOD; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D054876:Prenylation; D020537:RNA, Small Nucleolar / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020537:RNA, Small Nucleolar; D022661:RNA, Untranslated; D006160:Guanosine Triphosphate; D018631:ras Proteins