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BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

ABSTRACT: Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, at the posttranscriptional level. BAG3 interacted with HK2 mRNA, and the degree of BAG3 expression altered recruitment of the RNA-binding proteins Roquin and IMP3 to the HK2 mRNA. BAG3 knockdown destabilized HK2 mRNA via promotion of Roquin recruitment, whereas BAG3 overexpression stabilized HK2 mRNA via promotion of IMP3 recruitment. Collectively, our results show that BAG3 promotes reprogramming of glucose metabolism via interaction with HK2 mRNA in PDAC cells, suggesting that BAG3 may be a potential target in the aerobic glycolysis pathway for developing novel anticancer agents.

SUBMITTER: An MX

PROVIDER: S-EPMC5716268 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

An Ming-Xin MX Li Si S Yao Han-Bing HB Li Chao C Wang Jia-Mei JM Sun Jia J Li Xin-Yu XY Meng Xiao-Na XN Wang Hua-Qin HQ

The Journal of cell biology 20171107 12

Aerobic glycolysis, a phenomenon known historically as the Warburg effect, is one of the hallmarks of cancer cells. In this study, we characterized the role of BAG3 in aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) and its molecular mechanisms. Our data show that aberrant expression of BAG3 significantly contributes to the reprogramming of glucose metabolism in PDAC cells. Mechanistically, BAG3 increased Hexokinase 2 (HK2) expression, the first key enzyme involved in glycolysis, a ...[more]

PMID: 29114069

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Project description:BackgroundCircular RNAs (circRNAs) have been reported to play key roles in the development of various cancers. However, the biological functions and clinical significance of most circRNAs are still elusive. The purpose of this study was to explore the function and mechanism of a certain circRNA named circCDKN2B-AS1 in cervical cancer development and its potential value in the clinic.MethodsqRT-PCR was used to verify the expression level of circCDKN2B-AS1. CCK-8, Transwell, and flow cytometry (FCM) assays were performed to detect cellular proliferation, migration, and apoptosis, respectively. A Seahorse XFe96 Analyzer was used to measure glycolysis metabolism level. RNA pull-down, RNA immunoprecipitation (RIP), actinomycin-D addition assays and Western blotting were used to screen and elucidate the potential mechanisms involved. BALB/c nude mice and zebrafish embryos (AB, WT) were used as animal models to investigate tumorigenesis capability. 18FDG-microPET/CT imaging and lactic acid (LA) and pyruvic acid (PA) content detection assays were used to detect the level of glucose metabolism in subcutaneous tumors from nude mice.ResultsCircCDKN2B-AS1, a circular isoform of the long noncoding RNA (lncRNA) CDKN2B-AS1, was upregulated in cervical cancer and precancerous tissues. We found that circCDKN2B-AS1 associated with the IMP3 protein depending on a specific binding site and regulated the stability of Hexokinase 2 (HK2) mRNA, the rate-limiting enzyme of the aerobic glycolysis pathway. The expression level of circCDKN2B-AS1 fated the binding of IMP3 to the 3' untranslated region (UTR) of HK2 mRNA, consequently affecting the malignant cell phenotype and aerobic glycolysis in cervical cancer in vitro and in vivo. Mutant circCDKN2B-AS1, lacking the IMP3 binding site, did not have such effects. Utilization of an inhibitory peptide to block the interaction between circCDKN2B-AS1 and the IMP3 protein impeded the binding of IMP3 to the 3'UTR of HK2 mRNA and suppressed aerobic glycolysis in cervical cancer cells.ConclusionsOur findings demonstrate that circCDKN2B-AS1 facilitates aerobic glycolysis by sponging the IMP3 protein to stabilize HK2 mRNA, consequently promoting the malignant phenotype in cervical cancer, which may provide a potential approach for cervical cancer therapeutics.

Project description:Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.

Project description:Background:The stem cell factor SALL4 is reactivated in human cancers. SALL4 plays diverse roles in tumor growth, metastasis, and drug resistance, but its role in tumor metabolism has not been well characterized. Methods:The glycolytic levels of gastric cancer cells were detected by glucose uptake, lactate production, lactate dehydrogenase activity, ATP level, and hexokinase activity. QRT-PCR and western blot were used to detect the changes in the expression of glycolytic genes and proteins. The downstream target genes of SALL4 were identified by microarray. The regulation of hexokinase II (HK-2) by SALL4 was analyzed by luciferase reporter assay and chromatin immunoprecipitation assay. Transwell migration assay, matrigel invasion assay, cell counting assay and colony formation assay were used to study the roles of HK-2 regulation by SALL4 in gastric cancer cells in vitro. The effects of SALL4 on glycolysis and gastric cancer progression in vivo were determined by subcutaneous xenograft and peritoneal metastasis tumor models in nude mice. Results:SALL4 knockdown inhibited glucose uptake, lactate production, lactate dehydrogenase activity, ATP level and hexokinase activity in gastric cancer cells, and decreased the expression of glycolytic genes and proteins. Microarray analysis showed that SALL4 knockdown affected glycolysis-related pathway. The regulation of HK-2 gene expression by SALL4 was confirmed by luciferase reporter assay and chromatin immunoprecipitation assay. HK-2 knockdown abrogated the promotion of glycolysis by SALL4 in gastric cancer cells, indicating that HK-2 acts as a downstream effector of SALL4. Moreover, HK-2 knockdown reversed the promoting role of SALL4 in gastric cancer cell proliferation, migration and invasion, suggesting that SALL4 drives gastric cancer progression by upregulating HK-2. Conclusions:SALL4 promotes gastric cancer progression through HK-2-mediated glycolysis, which reveals a new mechanism for the oncogenic roles of SALL4 in cancer.

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BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

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BAG3 directly stabilizes Hexokinase 2 mRNA and promotes aerobic glycolysis in pancreatic cancer cells.

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