Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

Kuniaki Sato, Takaaki Masuda, Qingjiang Hu, Taro Tobo, Sarah Gillaspie, Atsushi Niida, Mackenzie Thornton, Yousuke Kuroda, Hidetoshi Eguchi, Takashi Nakagawa, Katsura Asano, Koshi Mimori

Research output: Contribution to journalArticle

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Abstract

Background: Translational reprogramming through controlled initiation from non-AUG start codons is considered a crucial driving force in tumorigenesis and tumor progression. However, its clinical impact and underlying mechanism are not fully understood. Methods: Using a bioinformatics approach, we identified translation initiation regulator 5MP1/BZW2 on chromosome 7p as a potential oncogenic driver gene in colorectal cancer (CRC), and explored the biological effect of 5MP1 in CRC in vitro or in vivo. Pathway analysis was performed to identify the downstream target of 5MP1, which was verified with transcriptomic and biochemical analyses. Finally, we assessed the clinical significance of 5MP1 expression in CRC patients. Findings: 5MP1 was ubiquitously amplified and overexpressed in CRC. 5MP1 promoted tumor growth and induced cell cycle progression of CRC. c-Myc was identified as its potential downstream effector. c-Myc has two in-frame start codons, AUG and CUG (non-AUG) located upstream of the AUG. 5MP1 expression increased the AUG-initiated c-Myc isoform relative to the CUG-initiated isoform. The AUG-initiated c-Myc isoform displayed higher protein stability and a stronger transactivation activity for oncogenic pathways than the CUG-initiated isoform, accounting for 5MP1-driven cell cycle progression and tumor growth. Clinically, high 5MP1 expression predicts poor survival of CRC patients. Interpretation: 5MP1 is a novel oncogene that reprograms c-Myc translation in CRC. 5MP1 could be a potential therapeutic target to overcome therapeutic resistance conferred by tumor heterogeneity of CRC. Fund: Japan Society for the Promotion of Science; Priority Issue on Post-K computer; National Institutes of Health; National Science Foundation; KSU Johnson Cancer Center.

Original languageEnglish
Pages (from-to)387-402
Number of pages16
JournalEBioMedicine
Volume44
DOIs
Publication statusPublished - Jun 1 2019

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Oncogenes
Tumors
Colorectal Neoplasms
Protein Isoforms
Phenotype
Cells
Initiator Codon
Neoplasms
Bioinformatics
Chromosomes
Cell Cycle
Genes
Health
Protein Stability
National Institutes of Health (U.S.)
Growth
Computational Biology
Transcriptional Activation
Japan
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer. / Sato, Kuniaki; Masuda, Takaaki; Hu, Qingjiang; Tobo, Taro; Gillaspie, Sarah; Niida, Atsushi; Thornton, Mackenzie; Kuroda, Yousuke; Eguchi, Hidetoshi; Nakagawa, Takashi; Asano, Katsura; Mimori, Koshi.

In: EBioMedicine, Vol. 44, 01.06.2019, p. 387-402.

Research output: Contribution to journalArticle

Sato, Kuniaki ; Masuda, Takaaki ; Hu, Qingjiang ; Tobo, Taro ; Gillaspie, Sarah ; Niida, Atsushi ; Thornton, Mackenzie ; Kuroda, Yousuke ; Eguchi, Hidetoshi ; Nakagawa, Takashi ; Asano, Katsura ; Mimori, Koshi. / Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer. In: EBioMedicine. 2019 ; Vol. 44. pp. 387-402.
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AU - Masuda, Takaaki

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AU - Gillaspie, Sarah

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AU - Thornton, Mackenzie

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