Cancer cells prefer glycolysis for energy metabolism, even when there is sufficient oxygen to make it unnecessary. This is called the Warburg effect, and it promotes tumorigenesis and malignant progression. In this study, we demonstrated that EZH2, a multifaceted oncogenic protein involved in tumor proliferation, invasion and metastasis, promotes glioblastoma tumorigenesis and malignant progression through activation of the Warburg effect. We observed that HIF1α is a target of EZH2 whose activation is necessary for EZH2-mediated metabolic adaption, and that HIF1α is activated upon EZH2 overexpression. EZH2 suppressed expression of EAF2, which in turn upregulated HIF1α levels. We conclude from these results that EZH2 promotes tumorigenesis and malignant progression in part by activating glycolysis through an EAF2-HIF1α signaling axis.

Glioblastoma stem-like cells (GSCs) play essential roles in glioma growth, radio- and chemo-resistance, and recurrence. Elimination of GSCs has therefore become a key strategy and challenge in glioblastoma therapy. Here, we show that melatonin, an indolamine derived from I-tryptophan, significantly inhibited viability and self-renewal ability of GSCs accompanied by a decrease of stem cell markers. We have identified EZH2-NOTCH1 signaling as the key signal pathway that regulated the effects of melatonin in the GSCs. Instead of transcriptionally silencing gene expression by generating a methylated epigenetic mark at histone 3 at lysine 27 (H3K27), EZH2 regulates NOTCH1 expression by directly binding to the NOTCH1 promoter. Moreover, correlation between the expressions of EZH2 and NOTCH intracellular domain 1 (NICD1) was observed in the clinical tumor samples, evidently supporting the existence of EZH2-NOTCH1 interaction in the gliomas and GSCs. Collectively, we demonstrated that melatonin, a potential tumor inhibitor, performs its function partly by suppressing GSC properties through EZH2-NOTCH1 signaling axis.

BackgroundCancer cells maintain energy metabolism mainly by glycolysis, even under sufficient oxygen conditions. It gives cancer cells better growth advantages under complicated internal environment. KPNA2 is a novel oncogene that has received much attention in recent years, but the exact mechanisms of KPNA2 in tumorigenesis and progression are largely unknown. Especially its potential roles in the metabolic transformation of tumors still remain to be explored.MethodsThe expressions of KPNA2 in glioblastoma and normal human brain samples were analyzed by immunohistochemical analysis. The activities of key enzymes in glycolysis, the production of lactate acid and glucose uptake were investigated by colorimetry. GLUT-1 expression was measured by flow cytometry. CCK8 was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of KPNA2 in vivo. In addition, Co-IP, subcellular fractionation, western blot, immunofluorescence and luciferase assay were used to investigate the internal connection between KPNA2, c-myc and E2F1.ResultsIn the present study, we found that KPNA2 was highly expressed in the glioma compared to the normal brain tissues. Level of KPNA2 was an independent predictor of prognosis in the glioma patients. Knockdown of KPNA2 in the glioblastoma cell lines U87 and U251 decreased deoxyglucose uptake, activities of the key glycolytic enzymes and lactate production. The level of oxidative phosphorylation (OXPHOS) was moderately decreased. Additioanlly, tumor proliferation and invasiveness were concomitantly downregulated. We have identified c-myc as a potential mediator of KPNA2. Aberrant expression of KPNA2 significantly changed the subcellular distribution of c-myc as well as its expression level. E2F1, another key cargo protein of KPNA2, was further identified to play a potential role in regulating the transcription of c-myc by KPNA2.ConclusionsOur findings suggested that KPNA2, a potential tumor oncogene, performs its function in part via regulating cellular metabolism through c-myc signaling axis. It would provide a possible explanation for Warburg effect and thus offer a new perspective to the roles of KPNA2 in gliomagenesis.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0861-9) contains supplementary material, which is available to authorized users.

It is well established that ncRNAs are emerging as important regulators in various types of cancers, however, their functions and contributions in cancers remain insufficiently defined. In this study, we reported the expression levels of a long noncoding RNA (lncRNA), named HSP90AA1-IT1 (HSP90AA1 intronic transcript 1), appeared to correlate with the pathological grades of gliomas and high level of HSP90AA1-IT1 indicated poor prognosis. Downregulation of HSP90AA1-IT1 in the glioma cell lines significantly suppressed cell viability, proliferation, EMT, invasion and migration in addition to an increase in apoptosis and aberrant cell cycle progression. The tumorigenic capacity of these cells in vivo were also inhibited. We further demonstrated that the oncogenic effects of HSP90AA1-IT1 could be mediated by a direct binding to miR-885-5p. Sharing the same binding sites with CDK2, a key regulator in gliomagenesis, HSP90AA1-IT1 competitively bound to miR-885-5p, thereby prevented CDK2 from miR-885-5p mediated post-transcriptional repression. Taken together, it is concluded that HSP90AA1-IT1, performs its function via regulating the development of gliomas through miR-885-5p-CDK2 signaling axis, and this has added new perspective to its role in tumorigenesis, thus providing potential therapeutic targets for glioma treatment.

Background Glioma is one of the most aggressive malignant brain tumors which is characterized with highly infiltrative growth and poor prognosis. NKAP (NF-κB activating protein) is a widely expressed 415-amino acid nuclear protein that is overexpressed by gliomas, but its function in glioma was still unknown. Methods CCK8 and EDU assay was used to examine the cell viability in vitro, and the xenograft models in nude mice were established to explore the roles of NAKP in vivo. The expressions of NKAP, Notch1 and SDF-1 were analyzed by immunofluorescence analysis. The expression of NKAP and Notch1 in glioma and normal human brain samples were analyzed by immunohistochemical analysis. In addition, CHIP, Gene chip, western blot, flow cytometry, immunofluorescence, ELISA and luciferase assay were used to investigate the internal connection between NKAP and Notch1. Results Here we showed that overexpression of NKAP in gliomas could promote tumor growth by contributing to a Notch1-dependent immune-suppressive tumor microenvironment. Downregulation of NKAP in gliomas had abrogated tumor growth and invasion in vitro and in vivo. Interestingly, compared to the control group, inhibiting NKAP set up obstacles to tumor-associated macrophage (TAM) polarization and recruitment by decreasing the secretion of SDF-1 and M-CSF. To identify the potential mechanisms involved, we performed RNA sequencing analysis and found that Notch1 appeared to positively correlate with the expression of NKAP. Furthermore, we proved that NKAP performed its function via directly binding to Notch1 promoter and trans-activating it. Notch1 inhibition could alleviate NKAP’s gliomagenesis effects. Conclusion these observations suggest that NKAP promotes glioma growth by TAM chemoattraction through upregulation of Notch1 and this finding introduces the potential utility of NKAP inhibitors for glioma therapy. Electronic supplementary material The online version of this article (10.1186/s13046-019-1281-1) contains supplementary material, which is available to authorized users.

Chemo-resistance is considered a key problem in triple negative breast cancer (TNBC) chemotherapy and as such, an urgent need exists to identify its exact mechanisms. Inhibitor of DNA binding factor 4 (ID4) was reported to play diverse roles in different breast cancer molecular phenotypes. In addition, ID4 was associated with mammary carcinoma drug resistance however its functions and contributions remain insufficiently defined. The expression of ID4 in MCF-7, MCF-7/Adr and MDA-MB-231 breast cancer cell lines and patients' tissues were detected by RT-PCR, western blot and immunohistochemistry. Furthermore, TCGA database was applied to confirm these results. Edu and CCK8 assay were performed to detect the proliferation and drug resistance in breast cancer cell lines. Transwell and scratch migration assay were used to detected metastasis. Western blot, TCGA database, Immunoprecipitation (IP), Chromatin Immunoprecipitation (ChIP) and Luciferase reporter assay were used to investigate the tumor promotion mechanisms of ID4. In this study, we report that the expression levels of ID4 appeared to correlate with breast cancers subtype differentiation biomarkers (including ER, PR) and chemo-resistance related proteins (including MRP1, ABCG2, P-gp). Down-regulation of ID4 in MCF-7/Adr and MDA-MB-231 breast cancer cell lines significantly suppressed cell proliferation and invasion, however enhanced Adriamycin sensitivity. We further demonstrated that the oncogenic and chemo-resistant effects of ID4 could be mediated by binding to CBF1 promoter region though combination with MyoD1, and then the downstream target MRP1 could be activated. We reveal for the first time that ID4 performs its function via a CBF1-MRP1 signaling axis, and this finding provides a novel perspective to find potential therapeutic targets for breast cancer chemotherapy.