Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma
Authors
- D.A. Hofman
- J. Ruiz-Orera
- I. Yannuzzi
- R. Murugesan
- A. Brown
- K.R. Clauser
- A.L. Condurat
- J.T. van Dinter
- S.A.G. Engels
- A. Goodale
- J. van der Lugt
- T. Abid
- L. Wang
- K.N. Zhou
- J. Vogelzang
- K.L. Ligon
- T.N. Phoenix
- J.A. Roth
- D.E Root
- N. Hubner
- T.R. Golub
- P. Bandopadhayay
- S. van Heesch
- J.R. Prensner
Journal
- Molecular Cell
Citation
- Mol Cell 84 (2): 261-276
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.