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

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

doi:10.1016/j.ebiom.2019.05.058

Abstract

BackgroundTranslational 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.MethodsUsing 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.Findings5MP1 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.Interpretation5MP1 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.FundJapan Society for the Promotion of Science; Priority Issue on Post-K computer; National Institutes of Health; National Science Foundation; KSU Johnson Cancer Center.

Highlights

Translation or mRNA-dependent protein synthesis is a crucial process of gene expression that directly determines the abundance of cellular proteome [1,2]
From a total of 426 genes located on chromosome 7p, we extracted 20 candidate genes that satisfied the two criteria: 1) overexpression in tumor tissues compared to non-neoplastic tissues (NNT) of colorectal mucosa (N 1.5-fold change, Mann-Whitney U test p b 0.01) and 2) positive correlation between DNA copy number and mRNA expression levels (Pearson correlation N0.4, p b 0.01)
We discovered that 5MP1 is a novel oncogene in colorectal cancer (CRC) and that its gain-of-function via amplification of its DNA copy number contributes to the tumor growth of CRC and poor prognosis in CRC patients

Summary

Introduction

Translation or mRNA-dependent protein synthesis is a crucial process of gene expression that directly determines the abundance of cellular proteome [1,2]. The initiation phase of translation governed by eukaryotic initiation factors (eIFs) is rate-limiting for protein synthesis, and considered to be the targets of translational control [5]. Several oncogenes such as c-Myc, mTOR, and RAS affect the activity of these factors and induce selective translation of mRNAs that encode proteins involved in proliferation, angiogenesis and stress responses [6,7]. 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. 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

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