TY - JOUR
T1 - Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer
AU - Sato, Kuniaki
AU - Masuda, Takaaki
AU - Hu, Qingjiang
AU - Tobo, Taro
AU - Gillaspie, Sarah
AU - Niida, Atsushi
AU - Thornton, Mackenzie
AU - Kuroda, Yohsuke
AU - Eguchi, Hidetoshi
AU - Nakagawa, Takashi
AU - Asano, Katsura
AU - Mimori, Koshi
N1 - Funding Information:
This work was supported in part by the following grants and foundations: Japan Society for the Promotion of Science [ 15H0912 , 15H05707 , 16K07177 , 16K10543 , 16K19197 , 17K16454 , 17K16521 , 17K10593 and 17K19608 ]; OITA Cancer Research Foundation ; Priority Issue on Post-K computer [hp170227, hp160219]; Eli Lilly Japan K.K. Grant; Grants from National Institutes of Health [ R15 GM124671 to K.A.]; Research grant from National Science Foundation [ MCB 1412550 to K.A.]; An Innovative Award from KSU Terry Johnson Cancer Center [to K.A.]; Faculty Development Awards from KSU [to K.A.]. S. G. and M. T. received K-INBRE scholarship [ National Institutes of Health , P20GM103418 ].
Funding Information:
This work was supported in part by the following grants and foundations: Japan Society for the Promotion of Science [15H0912, 15H05707, 16K07177, 16K10543, 16K19197, 17K16454, 17K16521, 17K10593 and 17K19608]; OITA Cancer Research Foundation; Priority Issue on Post-K computer [hp170227, hp160219]; Eli Lilly Japan K.K. Grant; Grants from National Institutes of Health [R15 GM124671 to K.A.]; Research grant from National Science Foundation [MCB 1412550 to K.A.]; An Innovative Award from KSU Terry Johnson Cancer Center [to K.A.]; Faculty Development Awards from KSU [to K.A.]. S. G. and M. T. received K-INBRE scholarship [National Institutes of Health, P20GM103418]. This work used the supercomputing resource provided by the Human Genome Center, The Institute of Medical Science, The University of Tokyo ( http://sc.hgc.jp/shirokane.html). We thank the Screening Committee of Anticancer Drugs in the Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology for the SCADS inhibitor kits; M. Oshiumi, M. Uto, K. Oda, M. Kasagi, S. Sakuma, N. Mishima, T. Kawano and C. R. Singh for their technical assistance; and Dr. Tyler Lahusen for helpful comments and English proofreading.
Funding Information:
This work was supported in part by the following grants and foundations: Japan Society for the Promotion of Science [15H0912, 15H05707, 16K07177, 16K10543, 16K19197, 17K16454, 17K16521, 17K10593 and 17K19608]; OITA Cancer Research Foundation; Priority Issue on Post-K computer [hp170227, hp160219]; Eli Lilly Japan K.K. Grant; Grants from National Institutes of Health [R15 GM124671 to K.A.]; Research grant from National Science Foundation [MCB 1412550 to K.A.]; An Innovative Award from KSU Terry Johnson Cancer Center [to K.A.]; Faculty Development Awards from KSU [to K.A.]. S. G. and M. T. received K-INBRE scholarship [National Institutes of Health, P20GM103418].
Funding Information:
We thank the Screening Committee of Anticancer Drugs in the Scientific Support Programs for Cancer Research Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology for the SCADS inhibitor kits; M. Oshiumi, M. Uto, K. Oda, M. Kasagi, S. Sakuma, N. Mishima, T. Kawano and C. R. Singh for their technical assistance; and Dr. Tyler Lahusen for helpful comments and English proofreading.
Publisher Copyright:
© 2019
PY - 2019/6
Y1 - 2019/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ebiom.2019.05.058
DO - 10.1016/j.ebiom.2019.05.058
M3 - Article
C2 - 31175057
AN - SCOPUS:85066501996
SN - 2352-3964
VL - 44
SP - 387
EP - 402
JO - EBioMedicine
JF - EBioMedicine
ER -
