A peptide encoded by upstream open reading frame of <i>MYC</i> binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant <i>MYC</i> transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) <i>MPEP</i>. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a <i>MYC</i>-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

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Publication Details

Journal
Science Translational Medicine
Published
2024-10-02
DOI
https://doi.org/10.1126/scitranslmed.adk9524
Citations
11
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
2.57
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article

A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

Yongping You, Maolei Zhang, Nu Zhang, Kailin Yang et al.
11 citations
Science Translational Medicine
RNA Research and Splicing
2.57
article

A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice

Yongping You, Maolei Zhang, Nu Zhang, Kailin Yang, Jeremy N. Rich, Qiulian Wu, Xiuxing Wang, Chenfei Lu, Xujia Wu, Deobrat Dixit, Xinya Gao, Sameer Agnihotri, Danling Gu, Yu Shi, Stephen C. Mack, Fanying Li, Ryan C. Gimple, Tiebang Kang, Michael D. Taylor
article en
11 citations

Abstract

MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant <i>MYC</i> transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) <i>MPEP</i>. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a <i>MYC</i>-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.

Science Translational MedicineVol. 16(767)
St. Jude Children's Research Hospital (US), Cleveland Clinic (US), Southwest University (CN), Sun Yat-sen University (CN), University of Pittsburgh (US), Washington University in St. Louis (US), National Health and Family Planning Commission (CN), Hospital for Sick Children (CA), University of California San Diego (US), Sanford Consortium for Regenerative Medicine (US), Brain Tumour Research (GB), Guangzhou Women and Children Medical Center (CN), Jiangsu Cancer Hospital (CN), UPMC Hillman Cancer Center (US), The First Affiliated Hospital, Sun Yat-sen University (CN), University of Pittsburgh Medical Center (US), Sun Yat-sen University Cancer Center (CN), Nanjing Medical University (CN), Guangzhou Medical University (CN)
No poverty
Openalex Percentile: Top 10%
RNA Research and Splicing
2.57
DOISourceOpenAlex
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