The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53

Abstract

Small nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.

Dysregulation of Small Nucleolar RNAs in B-Cell Malignancies

“…SNORA6, SNORA31, SNORA62, SNORA71C, SNORD37, and SNORD50B were significantly downregulated in CLL compared to normal total tonsillar B-cells. Downregulation of SNORD50B has also been observed in a variety of other human cancers, including breast cancer [ 90 ], lung cancer [ 91 ], melanoma [ 91 ] and T-cell lymphoma [ 91 ]. The expression of SNORA31 in CLL patients correlated with the expression of its host gene, tumor protein translationally controlled 1 (TPT1), which is an important target of TP53 [ 92 ].…”

“…SNORD50A and SNORD50B both directly bind and inhibit K-RAS . Deletion of these snoRNAs leads to an increased activity of oncogenic K-RAS signaling, suggesting a functional role for loss of these snoRNAs in CLL development [ 90 , 91 ]. In addition, the snoRNA host gene 5 (SNHG5), which harbors SNORD50A/B, is confirmed to regulate chemotherapy resistance by modulating the SNHG5/miR-32/DNAJB9 axis in AML patients [ 93 ].…”

The role of OncoSnoRNAs and Ribosomal RNA 2’-O-methylation in Cancer

“…More recently, it was reported that SNORD50A and SNORD50B also enhance the interaction between the ubiquitin ligase TRIM21 and its substrate GMPS subsequently influencing the interaction of GMPS with p53. Depending on p53 mutational status this interaction would either promote or inhibit malignant phenotype of breast cancer cells [ 128 ]. Another example is SNORD12B, a snoRNA predicted to target 28S-G3899(3878) [ 129 ].…”

Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs

“…Very interestingly, many other interactions with functional outcomes have been identified in the last years. The SNORD50A-SNORD50B locus produces snoRNAs that interact with the FIP1 subunit of the cleavage and polyadenylation specificity factor (CPSF) to modulate mRNA 3 -end processing [221], with the proto-oncogene KRAS to inhibit its activity [222,223] or with the E3 ubiquitin ligase TRIM21 and its substrate Guanosine 5 -monophosphate synthase (GMPS) to increase their interaction [224]. Numerous C/D and H/ACA snoRNAs have been proposed to interact with the poly-ADPribosyltransferase PARP1 independently of DNA damage and to stimulate its catalytic activity in the nucleolus, leading to ADP-ribosylation of the RNA helicase DDX21 and increased rDNA transcription [225].…”