Implications of RNA pseudouridylation for cancer biology and therapeutics: a narrative review

BackgroundPseudouridine (Psi), a C5-glycoside isomer of uridine, stands as one of the most prevalent RNA modifications in all RNA types. Distinguishing from the C-N bond linking uridine to ribose, the link between Psi and ribose is a C-C bond, endowing Psi modified RNA distinct properties and functions in various biological processes. The conversion of uridine to Psi is governed by pseudouridine synthases (PUSs). RNA pseudouridylation is implicated in cancer biology and therapeutics.ObjectivesIn this review, we will summarize the methods for detecting Psi, the process of Psi generation, the impact of Psi modification on RNA metabolism and gene expression, the roles of dysregulated Psi and pseudouridine synthases in cancers, and the underlying mechanism.MethodsWe conducted a comprehensive search of PubMed from its inception through February 2024. The search terms included "pseudouridine"; "pseudouridine synthase"; "PUS"; "dyskerin"; "cancer"; "tumor"; "carcinoma"; "malignancy"; "tumorigenesis"; "biomarker"; "prognosis" and "therapy". We included studies published in peer-reviewed journals that focused on Psi detection, specific mechanisms involving Psi and PUSs, and prognosis in cancer patients with high Psi expression. We excluded studies lacking sufficient methodological details or appropriate controls.Results Psi has been recognized as a significant biomarker in cancer diagnosis and prognosis. Abnormal Psi modifications mediated by various PUSs result in dysregulated RNA metabolism and impaired RNA function, promoting the development of various cancers. Overexpression of PUSs is common in cancer cells and predicts poor prognosis. PUSs inhibition arrests cell proliferation and enhances apoptosis in cancer cells, suggesting PUS-targeting cancer therapy may be a potential strategy in cancer treatment.DiscussionHigh Psi levels in serum, urine, and saliva may suggest cancer, but do not specify the type, requiring additional lab markers and imaging for accurate diagnosis. Standardized detection methods are also crucial for reliable results. PUSs are linked to cancer, but more researches are needed to understand their mechanisms in different cancers. Anticancer treatments targeting PUSs are still under developed.