Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.
Authors | |
Keywords | |
Abstract | A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets. |
Year of Publication | 2024
|
Journal | Molecular cell
|
Volume | 84
|
Issue | 2
|
Pages | 261-276.e18
|
Date Published | 01/2024
|
ISSN | 1097-4164
|
DOI | 10.1016/j.molcel.2023.12.003
|
PubMed ID | 38176414
|
Links |