Journal article
Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming
Nature cancer, Vol.5(7), pp.1024-1044
03/22/2024
DOI: 10.1038/s43018-024-00748-7
PMCID: PMC11552442
PMID: 38519786
Abstract
Cancers commonly reprogram translation and metabolism, but little is known about how these two features coordinate in cancer stem cells. Here we show that glioblastoma stem cells (GSCs) display elevated protein translation. To dissect underlying mechanisms, we performed a CRISPR screen and identified YRDC as the top essential transfer RNA (tRNA) modification enzyme in GSCs. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species (A denotes adenosine, and N denotes any nucleotide). Targeting YRDC reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine is an essential substrate of YRDC. Threonine accumulated in GSCs, which facilitated t6A formation through YRDC and shifted the proteome to support mitosis-related genes with ANN codon bias. Dietary threonine restriction (TR) reduced tumor t6A formation, slowed xenograft growth and augmented anti-tumor efficacy of chemotherapy and anti-mitotic therapy, providing a molecular basis for a dietary intervention in cancer treatment.
Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.
Details
- Title: Subtitle
- Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming
- Creators
- Xujia Wu - University of Pittsburgh Medical CenterHuairui Yuan - UPMC Hillman Cancer CenterQiulian Wu - University of Pittsburgh Medical CenterYixin Gao - Sun Yat-sen UniversityTingting Duan - University of Pittsburgh Medical CenterKailin Yang - Cleveland ClinicTengfei Huang - University of Pittsburgh Medical CenterShuai Wang - UPMC Hillman Cancer CenterFanen Yuan - University of Pittsburgh Medical CenterDerrick Lee - UPMC Hillman Cancer CenterSuchet Taori - University of Pittsburgh Medical CenterTritan Plute - University of PittsburghSoren Heissel - Rockefeller UniversityHanan Alwaseem - Rockefeller UniversityMichael Isay-Del Viscio - Rockefeller UniversityHenrik Molina - Rockefeller UniversitySameer Agnihotri - University of PittsburghDennis J. Hsu - University of PittsburghNu Zhang - Sun Yat-sen UniversityJeremy N. Rich - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Nature cancer, Vol.5(7), pp.1024-1044
- DOI
- 10.1038/s43018-024-00748-7
- PMID
- 38519786
- PMCID
- PMC11552442
- NLM abbreviation
- Nat Cancer
- ISSN
- 2662-1347
- eISSN
- 2662-1347
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 43
- Grant note
- Defense Health Agency 82192894 / Guangdong Province Regional Joint Fund-Key Project R35CA197718; R01CA238662; R01CA268634; R01NS103434 / University of Pittsburgh HT9425-23-1-0689 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 82341007 / National Natural Science Distinguished Youth Foundation of China 2022B1515120023 / Special Funds of the National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Science and Technology Planning Project of Guangzhou 202103000019 / Major Program of the National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) American Cancer Society 82125024 / U.S. Department of Health & Human Services | National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; Office of the Administrator (NIH)
- Language
- English
- Date published
- 03/22/2024
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984696708802771
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