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

Autor:	Hofman DA; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands.; These authors contributed equally., Ruiz-Orera J; Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.; These authors contributed equally., Yannuzzi I; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Murugesan R; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Brown A; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Current address: Arbor Biotechnologies, Cambridge, MA, 02140, USA., Clauser KR; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Condurat AL; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., van Dinter JT; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands., Engels SAG; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands., Goodale A; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., van der Lugt J; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands., Abid T; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Wang L; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Zhou KN; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Current address: Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA, 91101, USA., Vogelzang J; Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02215, USA., Ligon KL; Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02215, USA.; Department of Pathology, Boston Children's Hospital, Boston MA 02115., Phoenix TN; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45229, USA., Roth JA; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Root DE; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Hubner N; Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.; Charité-Universitätsmedizin, 10117 Berlin, Germany.; German Centre for Cardiovascular Research, Partner Site Berlin, 13347 Berlin, Germany., Golub TR; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA., Bandopadhayay P; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA., van Heesch S; Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS, Utrecht, the Netherlands., Prensner JR; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02115, USA.; Current address: Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 May 06. Date of Electronic Publication: 2023 May 06.
DOI:	10.1101/2023.05.04.539399
Abstrakt:	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. 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 step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for 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 cancer genomics studies seeking to define new cancer targets. Competing Interests: Declaration of interests K.L.L. reports the following interests: equity in Travera; research funds from Bristol Myers Squibb, SEngine Precision Medicine, Multiple Myeloma Research Foundation and Eli Lilly and Company; and being a consultant or on the scientific advisory board for Bristol Myers Squibb, Travera, and IntegraGen. P.B. receives grant funding from Novartis Institute of Biomedical Research, and has received grant funding from Deerfield Therapeutics, both for unrelated projects. P.B. has also served on a paid advisory board for QED Therapeutics, unrelated to this work. D.E.R. receives research funding from members of the Functional Genomics Consortium (Abbvie, BMS, Jannsen, Merck, Vir), and is a director of Addgene, Inc.
Databáze:	MEDLINE
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