Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

Hofman, D.A.; Ruiz-Orera, J.; Yannuzzi, I.; Murugesan, R.; Brown, A.; Clauser, K.R.; Condurat, A.L.; van Dinter, J.T.; Engels, S.A.G.; Goodale, A.; van der Lugt, J.; Abid, T.; Wang, L.; Zhou, K.N.; Vogelzang, J.; Ligon, K.L.; Phoenix, T.N.; Roth, J.A.; Root, D.E; Hubner, N.; Golub, T.R.; Bandopadhayay, P.; van Heesch, S.; Prensner, J.R.

Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

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Item Type:	Article
Title:	Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma
Creators:	Hofman, D.A., Ruiz-Orera, J. ORCID: https://orcid.org/0000-0002-8317-0034, Yannuzzi, I., Murugesan, R., Brown, A., Clauser, K.R., Condurat, A.L., van Dinter, J.T., Engels, S.A.G., Goodale, A., van der Lugt, J., Abid, T., Wang, L., Zhou, K.N., Vogelzang, J., Ligon, K.L., Phoenix, T.N., Roth, J.A., Root, D.E, Hubner, N. ORCID: https://orcid.org/0000-0002-1218-6223, Golub, T.R., Bandopadhayay, P., van Heesch, S. and Prensner, J.R.
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.
Keywords:	Cancer, Gene Dependency, CRISPR, Medulloblastoma, Non-Canonical ORFs, Ribo-Seq, Translational Regulation, lncRNAs, uORF
Source:	Molecular Cell
ISSN:	1097-2765
Publisher:	Cell Press
Volume:	84
Number:	2
Page Range:	261-276
Date:	18 January 2024
Official Publication:	https://doi.org/10.1016/j.molcel.2023.12.003
PubMed:	View item in PubMed

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