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

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.

Protein and Signaling Pathway Responses to rhIL-6 Intervention Before Lobaplatin Treatment in Osteosarcoma Cells

“…Another protein, FUBP1, has been described as an oncoprotein in solid tumor entities as well as many other cancers, promoting tumorigenesis, proliferation, and metastasis of malignant cells ( 22 – 26 ). The silencing of FUBP1 could advance chemosensitivity to adriamycin in gastric cancer ( 27 ), and the expression of this protein in B-cell non-Hodgkin lymphoma is associated with cell adhesion-mediated drug resistance ( 28 ).…”

Multiple Functions of Fubp1 in Cell Cycle Progression and Cell Survival

“…Although three nuclear localization signals (NLS) confers the enrichment of Fubp1 in the nucleus [ 2 ], Fubp1 could translocate to the cytoplasm under various stimuli including viral infection and apoptosis to control mRNA stability or translation of its target genes [ 3 , 4 ]. Increasing evidence has demonstrated the oncogenic role of Fubp1 and deregulated expression of FUBP1 has been reported in several types of tumors, including hepatocellular carcinoma [ 5 , 6 ], nasopharyngeal carcinoma [ 7 ], gastric cancer [ 8 ], leukemia [ 9 ] and neuroblastoma [ 10 ]. The molecular mechanisms by which FUBP1 contributes to tumor propagation are currently being investigated.…”

Overexpression of FUBP1 is associated with human cervical carcinoma development and prognosis

“…FUBP1 is generally considered to be a transcription factor that promotes c-Myc expression. Moreover, our recent studies have shown that elevated FUBP1 accelerated glycolysis by binding with VHL promoter [18]. Whether FUBP1 act as a transcription factor to promote the expression of PRKDC deserves further investigation.…”

“…Other studies have also revealed that the abnormal expression of FUBP1 may not be related to the regulation of c-Myc in prostate and bladder cancers [17]. Our recent studies have shown that elevated FUBP1 inhibits the degradation of HIF1 α by binding with VHL promoter, thus accelerating glycolysis and leading to neuroblastoma cell proliferation [18]. However, the expression and role of FUBP1 in cervical carcinoma has never been reported.…”