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J Exp Clin Cancer Res. 2019 Sep 11;38(1):400. doi: 10.1186/s13046-019-1414-6.

FUBP1 promotes neuroblastoma proliferation via enhancing glycolysis-a new possible marker of malignancy for neuroblastoma.

Jiang P1,2, Huang M1,2, Qi W2, Wang F1, Yang T1, Gao T3, Luo C2, Deng J2, Yang Z2, Zhou T2, Zou Y1, Gao G4,5,6, Yang X7,8,9.

Author information

1
Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
2
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.
3
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
4
Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. gaogq@mail.sysu.edu.cn.
5
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. gaogq@mail.sysu.edu.cn.
6
Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products, Sun Yat-sen University, Guangzhou, China. gaogq@mail.sysu.edu.cn.
7
Program of Molecular Medicine, Affiliated Guangzhou Women and Children's Medical Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. yangxia@mail.sysu.edu.cn.
8
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. yangxia@mail.sysu.edu.cn.
9
Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. yangxia@mail.sysu.edu.cn.

Abstract

BACKGROUND:

Neuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20-30% of NB patients, indicating there might be other oncogenes in the development of NB. The far upstream element binding protein 1 (FUBP1) was first identified as a transcriptional regulator of the proto-oncogene MYC. However, the expression and role of FUBP1 in NB have not been documented.

METHODS:

FUBP1 expression was analysed from GEO database and verified by immunohistochemistry (IHC) and western blotting (WB) in NB tissues and cell lines. Cell proliferation and apoptosis were detected by Cell Counting Kit-8, Colony formation assay, EDU, TUNEL staining and flow cytometric analysis. Several glycolytic metabolites production was confirmed by ELISA and oxygen consuming rate (OCR). Luciferase assay, WB, chromatin immunoprecipitation (CHIP) were used to explore the mechanisms of the effect of FUBP1 on NB.

RESULTS:

FUBP1 mRNA levels were increased along with the increase in International Neuroblastoma Staging System (INSS) stages. High expression of FUBP1 with low N-Myc expression accounted for 44.6% of NB patient samples (n = 65). In addition, FUBP1 protein levels were remarkably increased with NB malignancy in the NB tissue microarray (NB: n = 65; ganglioneuroblastoma: n = 31; ganglioneuroma: n = 27). Furthermore, FUBP1 expression was negatively correlated with patient survival rate but positively correlated with ki67 content. In vitro experiments showed that FUBP1 promotes NB cell proliferation and inhibits cell apoptosis via enhancing glycolysis and ATP production. Mechanistically, FUBP1 inhibited the degradation of HIF1α via downregulation of Von Hippel-Lindau (VHL), the E3 ligase for HIF1α, resulting in upregulation of lactate dehydrogenase isoform B (LDHB) expression to enhance glycolysis. Overexpressed or silenced N-Myc could not regulate FUBP1 or LDHB levels.

CONCLUSIONS:

Taken together, our findings demonstrate for the first time that elevated FUBP1 promotes NB glycolysis and growth by targeting HIF1α rather than N-Myc, suggesting that FUBP1 is a novel and powerful oncogene in the development of NB independent of N-Myc and may have potential in the diagnosis and treatment of NB.

KEYWORDS:

C-Myc; FUBP1; Glycolysis; HIF1α; Neuroblastoma; VHL

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