Kral, Alexander, Jia, Lu, Sim, GeunYoung, Wan, Ledong, Krainer, Adrian (April 2025) Splice-switching ASOs targeting an Alu-derived exon in the AURKA 5'UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer. bioRxiv. ISSN 2692-8205 (Submitted)
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, such as SRSF1, MYC, and AURKA. Although KRAS-targeted therapies are in development, resistance mechanisms underscore the need to identify alternative vulnerabilities. Here, we uncover an SRSF1-AURKA-MYC oncogenic circuit, wherein SRSF1 regulates AURKA 5'UTR alternative splicing, enhancing AURKA protein expression; AURKA positively regulates SRSF1 and MYC post-translationally, independently of its kinase activity; and MYC in turn transcriptionally upregulates both SRSF1 and AURKA. Elevated SRSF1 in tumor cells promotes inclusion of an exonized Alu exon in the AURKA 5'UTR, resulting in splicing-dependent mRNA accumulation and exon-junction-complex deposition. Modulating 5'UTR splicing with splice-switching antisense oligonucleotides (ASOs) collapses the oncogenic circuit, reducing PDAC cell viability and triggering apoptosis. Our findings identify AURKA alternative splicing as a critical regulatory node and highlight ASO-mediated splice-switching as a potential therapeutic strategy that simultaneously targets SRSF1, AURKA, and MYC oncogenes.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 15 April 2025 |
| Date Deposited: | 16 Apr 2025 18:21 |
| Last Modified: | 18 Apr 2025 15:13 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41850 |
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