Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context
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 i...
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Format: | Article |
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Elsevier
2019-06-01
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Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419303664 |
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doaj-2de3a6e8311344458ad956e83ed0a466 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kuniaki Sato Takaaki Masuda Qingjiang Hu Taro Tobo Sarah Gillaspie Atsushi Niida Mackenzie Thornton Yousuke Kuroda Hidetoshi Eguchi Takashi Nakagawa Katsura Asano Koshi Mimori |
spellingShingle |
Kuniaki Sato Takaaki Masuda Qingjiang Hu Taro Tobo Sarah Gillaspie Atsushi Niida Mackenzie Thornton Yousuke Kuroda Hidetoshi Eguchi Takashi Nakagawa Katsura Asano Koshi Mimori Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context EBioMedicine |
author_facet |
Kuniaki Sato Takaaki Masuda Qingjiang Hu Taro Tobo Sarah Gillaspie Atsushi Niida Mackenzie Thornton Yousuke Kuroda Hidetoshi Eguchi Takashi Nakagawa Katsura Asano Koshi Mimori |
author_sort |
Kuniaki Sato |
title |
Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context |
title_short |
Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context |
title_full |
Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context |
title_fullStr |
Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context |
title_full_unstemmed |
Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in context |
title_sort |
novel oncogene 5mp1 reprograms c-myc translation initiation to drive malignant phenotypes in colorectal cancerresearch in context |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2019-06-01 |
description |
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. Keywords: Translational reprogramming, Colorectal cancer, 5MP1, c-Myc, Tumor heterogeneity, Oncogene |
url |
http://www.sciencedirect.com/science/article/pii/S2352396419303664 |
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doaj-2de3a6e8311344458ad956e83ed0a4662020-11-25T02:32:51ZengElsevierEBioMedicine2352-39642019-06-0144387402Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancerResearch in contextKuniaki Sato0Takaaki Masuda1Qingjiang Hu2Taro Tobo3Sarah Gillaspie4Atsushi Niida5Mackenzie Thornton6Yousuke Kuroda7Hidetoshi Eguchi8Takashi Nakagawa9Katsura Asano10Koshi Mimori11Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, Japan; Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Higashi-ku, Fukuoka, Fukuoka 860-8556, JapanDepartment of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, JapanDepartment of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, JapanDepartment of Clinical Laboratory Medicine and Pathology, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, JapanMolecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USADivision of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, JapanMolecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USADepartment of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, JapanDepartment of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, JapanDepartment of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Higashi-ku, Fukuoka, Fukuoka 860-8556, JapanMolecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA; Corresponding author at: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.Department of Surgery, Kyushu University Beppu Hospital, 4546 Tsurumihara, Beppu, Oita 874-0838, Japan; Corresponding author at: Department of Surgery, Beppu Hospital, Kyushu University, 4546, Tsurumihara, Beppu, Oita 874-0838, Japan.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. Keywords: Translational reprogramming, Colorectal cancer, 5MP1, c-Myc, Tumor heterogeneity, Oncogenehttp://www.sciencedirect.com/science/article/pii/S2352396419303664 |