NOVA1 acts as an oncogenic RNA- binding protein to regulate cholesterol homeostasis in human glioblastoma cells

• 成果类型: Article
• 署名作者: Saito, Yuhki; Yang, Yanhong; Saito, Misa; Park, Christopher Y.; Funato, Kosuke; Tabar, Viviane; Darnell, Robert B.
• 署名单位: Howard Hughes Medical Institute; Rockefeller University; Rockefeller University; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Simons Foundation; Flatiron Institute; University System of Georgia; University of Georgia
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13068
• DOI: 10.1073/pnas.2314695121
• 发表日期: 2024-02-28
• 关键词: immunity; antigen; ri

摘要

NOVA1 is a neuronal RNA- binding protein identified as the target antigen of a rare autoimmune disorder associated with cancer and neurological symptoms, termed paraneoplastic opsoclonus- myoclonus ataxia. Despite the strong association between NOVA1 and cancer, it has been unclear how NOVA1 function might contribute to cancer biology. In this study, we find that NOVA1 acts as an oncogenic factor in a GBM (glioblastoma multiforme) cell line established from a patient. Interestingly, NOVA1 and Argonaute (AGO) CLIP identified common 3 ' untranslated region (UTR) targets, which were down- regulated in NOVA1 knockdown GBM cells, indicating a transcriptome-wide intersection of NOVA1 and AGO-microRNA (miRNA) targets regulation. NOVA1 binding to 3 ' UTR targets stabilized transcripts including those encoding cholesterol homeostasis related proteins. Selective inhibition of NOVA1-RNA interactions with antisense oligonucleotides disrupted GBM cancer cell fitness. The precision of our GBM CLIP studies point to both mechanism and precise RNA sequence sites to selectively inhibit oncogenic NOVA1-RNA interactions. Taken together, we find that NOVA1 commonly overexpressed in GBM, where it can antagonize AGO2-miRNA actions and consequently up- regulates cholesterol synthesis, promoting cell viability.