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A single H/ACA small nucleolar RNA mediates tumor suppression downstream of oncogenic RAS
Mary McMahon1, Adrian Contreras1, Mikael Holm2
1Helen Diller Family Comprehensive Cancer Center, Department of Urology, University of California, San Francisco, San Francisco, United States.
Abstract:
Small nucleolar RNAs (snoRNAs) are a diverse group of non-coding RNAs that direct chemical modifications at specific residues on other RNA molecules, primarily on ribosomal RNA (rRNA). SnoRNAs are altered in several cancers; however, their role in cell homeostasis as well as in cellular transformation remains poorly explored. Here, we show that specific subsets of snoRNAs are differentially regulated during the earliest cellular response to oncogenic RASG12V expression. We describe a novel function for one H/ACA snoRNA, SNORA24, which guides two pseudouridine modifications within the small ribosomal subunit, in RAS-induced senescence in vivo. We find that in mouse models, loss of Snora24 cooperates with RASG12V to promote the development of liver cancer that closely resembles human steatohepatitic hepatocellular carcinoma (HCC). From a clinical perspective, we further show that human HCCs with low SNORA24 expression display increased lipid content and are associated with poor patient survival. We next asked whether ribosomes lacking SNORA24-guided pseudouridine modifications on 18S rRNA have alterations in their biophysical properties. Single-molecule Fluorescence Resonance Energy Transfer (FRET) analyses revealed that these ribosomes exhibit perturbations in aminoacyl-transfer RNA (aa-tRNA) selection and altered pre-translocation ribosome complex dynamics. Furthermore, we find that HCC cells lacking SNORA24-guided pseudouridine modifications have increased translational miscoding and stop codon readthrough frequencies. These findings highlight a role for specific snoRNAs in safeguarding against oncogenic insult and demonstrate a functional link between H/ACA snoRNAs regulated by RAS and the biophysical properties of ribosomes in cancer.
Insights
Small nucleolar RNAs (snoRNAs) are crucial for cell stability. Loss of SNORA24 snoRNA, alongside oncogenic RAS, drives liver cancer (HCC) by altering ribosome function and increasing translation errors.
Area of Science:
- Molecular Biology
- Cancer Research
- RNA Biology
Background:
- Small nucleolar RNAs (snoRNAs) regulate RNA modifications, primarily in ribosomal RNA (rRNA).
- Dysregulation of snoRNAs is observed in various cancers, but their precise roles in homeostasis and transformation are not fully understood.
- Oncogenic RAS signaling profoundly impacts cellular processes, yet its earliest effects on snoRNA expression and function remain largely unexplored.
Purpose of the Study:
- To investigate the role of snoRNAs in the early cellular response to oncogenic RAS.
- To elucidate the function of the H/ACA snoRNA SNORA24 in RAS-induced senescence and liver cancer development.
- To determine the impact of SNORA24-guided modifications on ribosome biophysical properties and translation fidelity in hepatocellular carcinoma (HCC).
Main Methods:
- Differential expression analysis of snoRNAs in response to oncogenic RAS G12V.
- In vivo studies using mouse models to assess the cooperative effect of Snora24 loss and RAS G12V in liver cancer.
- Clinical analysis of human HCC tissues to correlate SNORA24 expression with lipid content and patient survival.
- Single-molecule Fluorescence Resonance Energy Transfer (FRET) to analyze ribosome biophysical properties and dynamics.
- Assessment of translational miscoding and stop codon readthrough in HCC cells lacking SNORA24-guided modifications.
Main Results:
- Specific snoRNAs are differentially regulated upon oncogenic RAS G12V expression.
- Loss of SNORA24 cooperates with RAS G12V to promote steatohepatitic HCC development in mice.
- Low SNORA24 expression in human HCC correlates with increased lipid content and poorer patient survival.
- Ribosomes lacking SNORA24-guided pseudouridine modifications exhibit altered aa-tRNA selection and ribosome complex dynamics.
- HCC cells with deficient SNORA24 modifications show increased translational miscoding and stop codon readthrough.
Conclusions:
- SNORA24 plays a critical role in RAS-induced senescence and acts as a tumor suppressor in liver cancer.
- RAS-regulated H/ACA snoRNAs, like SNORA24, influence ribosome biophysical properties, impacting translation fidelity.
- These findings reveal a novel mechanism by which snoRNAs safeguard against oncogenic insults and highlight their potential as therapeutic targets in HCC.
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