Human snoRNA-93 is processed into a microRNA-like RNA that promotes breast cancer cell invasion

Genetic searches for tumor suppressors have recently linked small nucleolar RNA misregulations with tumorigenesis. In addition to their classically defined functions, several small nucleolar RNAs are now known to be processed into short microRNA-like fragments called small nucleolar RNA-derived RNAs. To determine if any small nucleolar RNA-derived RNAs contribute to breast malignancy, we recently performed a RNA-seq-based comparison of the small nucleolar RNA-derived RNAs of two breast cancer cell lines (MCF-7 and MDA-MB-231) and identified small nucleolar RNA-derived RNAs derived from 13 small nucleolar RNAs overexpressed in MDA-MB-231s. Importantly, we find that inhibiting the most differentially expressed of these small nucleolar RNA-derived RNAs (sdRNA-93) in MDA-MB-231 cells results primarily in a loss of invasiveness, whereas increased sdRNA-93 expression in either cell line conversely results in strikingly enhanced invasion. Excitingly, we recently determined sdRNA-93 expressions in small RNA-seq data corresponding to 116 patient tumors and normal breast controls, and while we find little sdRNA-93 expression in any of the controls and only sporadic expression in most subtypes, we find robust expression of sdRNA-93 in 92.8% of Luminal B Her2+tumors. Of note, our analyses also indicate that at least one of sdRNA-93’s endogenous roles is to regulate the expression of Pipox, a sarcosine metabolism-related protein whose expression significantly correlates with distinct molecular subtypes of breast cancer. We find sdRNA-93 can regulate the Pipox 3′UTR via standard reporter assays and that manipulating endogenous sdRNA-93 levels inversely correlates with altered Pipox expression. In summary, our results strongly indicate that sdRNA-93 expression actively contributes to the malignant phenotype of breast cancer through participating in microRNA-like regulation. A short microRNA-like fragment excised from a small nucleolar RNA (called a snoRNA-derived RNA or sdRNA) contributes to the invasiveness of breast cancer cells. Glen Borchert from the University of South Alabama, USA, and colleagues compared the expression of sdRNAs between a primary breast cancer cell line and a metastatic one. They identified 13 sdRNAs with markedly different abundances. Blocking the sdRNA with the biggest expression differential sdRNA-93-decreased cellular invasion, whereas increasing its abundance enhanced tumor cell invasiveness. Looking at human tissues, sdRNA-93 was routinely expressed in biopsies taken from patients with the luminal HER2-positive form of breast cancer, less often in other tumor types and almost never in healthy breast samples. Hinting at its function, the researchers showed that sdRNA-93 targets and regulates a gene contributing to specific molecular subtypes of breast cancer.