LncRNA-MIF, a c-Myc-activated long non-coding RNA, suppresses glycolysis by promoting Fbxw7-mediated c-Myc degradation.
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ABSTRACT:
SUBMITTER: Zhang P
PROVIDER: S-EPMC4967955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Colorectal cancer (CRC), a common tumor, is characterized by a high mortality rate. Long non-coding RNA maternally expressed gene 3 (MEG3) serves a regulatory role in the carcinogenesis and progression of several types of cancer; however, its role in CRC remains largely unknown. The aim of this study was to explore the regulatory role and mechanism(s) of MEG3 in CRC. The Warburg effect or aerobic glycolysis is characteristic of the metabolism of tumor cells. To determine the effect of MEG3 on glycolysis of CRC cells, we used an XF analyzer to perform glycolysis stress test assays and found that overexpression of MEG3 significantly inhibited glycolysis, glycolytic capacity, as well as lactate production in CRC cells, whereas knockdown of MEG3 produced the opposite effect. Mechanistically, overexpression of MEG3 induced ubiquitin-dependent degradation of c-Myc and inhibited c-Myc target genes involved in the glycolysis pathway such as lactate dehydrogenase A, pyruvate kinase muscle 2, and hexokinase 2. Moreover, we found that MEG3 can be activated by vitamin D and vitamin D receptor (VDR). Clinical data demonstrated that MEG3 was positively associated with serum vitamin D concentrations in patients with CRC. We found that 1,25(OH)2D3 treatment increased MEG3 expression, and knockdown of VDR abolished the effect of MEG3 on glycolysis. These results indicate that vitamin D-activated MEG3 suppresses aerobic glycolysis in CRC cells via degradation of c-Myc. Thus, vitamin D may have therapeutic value in the treatment of CRC.
| S-EPMC7078156 | biostudies-literature
Project description:Gastric cancer (GC) remains a threat to public health with high incidence and mortality worldwide. Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) play critical regulatory roles in cancer biology, including GC. Previous profiling study showed that lncRNA linc00261 was aberrantly expressed in GC. However, the role of linc00261 in GC progression and the precise molecular mechanism remain unknown. In this study, we report that linc00261 was significantly down-regulated in GC tissues and the expression level of linc00261 negatively correlated with advanced tumour status and clinical stage as well as poor prognostic outcome. In vitro functional assays indicate that ectopic expression of linc00261 suppressed cell invasion by inhibiting the epithelial-mesenchymal transition (EMT). By RNA pull-down and mass spectrum experiments, we identified Slug as an RNA-binding protein that binds to linc00261. We confirmed that linc00261 down-regulated Slug by decreasing the stability of Slug proteins and that the tumour-suppressive function of linc00261 can be neutralized by Slug. linc00261 may promote the degradation of Slug via enhancing the interaction between GSK3? and Slug. Moreover, linc00216 overexpression repressed lung metastasis in vivo. Together, our findings suggest that linc00261 acts a tumour suppressor in GC by decreasing the stability of Slug proteins and suppressing EMT. By clarifying the mechanisms underlying GC progression, these findings may facilitate the development of novel therapeutic strategies for GC.
| S-EPMC5387161 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
| S-EPMC7067692 | biostudies-literature
Project description:Background & aimsThe ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is recognized as a tumor suppressor in many cancer types due to its ability to promote the degradation of numerous oncogenic target proteins. Herein, we aimed to elucidate its role in intrahepatic cholangiocarcinoma (iCCA).MethodsHerein, we first confirmed that FBXW7 gene expression was reduced in human iCCA specimens. To identify the molecular mechanisms by which FBXW7 dysfunction promotes cholangiocarcinogenesis, we generated a mouse model by hydrodynamic tail vein injection of Fbxw7ΔF, a dominant negative form of Fbxw7, either alone or in association with an activated/myristylated form of AKT (myr-AKT). We then confirmed the role of c-MYC in human iCCA cell lines and its relationship to FBXW7 expression in human iCCA specimens.ResultsFBXW7 mRNA expression is almost ubiquitously downregulated in human iCCA specimens. While forced overexpression of Fbxw7ΔF alone did not induce any appreciable abnormality in the mouse liver, co-expression with AKT triggered cholangiocarcinogenesis and mice had to be euthanized by 15 weeks post-injection. At the molecular level, a strong induction of Fbxw7 canonical targets, including Yap, Notch2, and c-Myc oncoproteins, was detected. However, only c-MYC was consistently confirmed as a FBXW7 target in human CCA cell lines. Most importantly, selected ablation of c-Myc completely impaired iCCA formation in AKT/Fbxw7ΔF mice, whereas deletion of either Yap or Notch2 only delayed tumorigenesis in the same model. In human iCCA specimens, an inverse correlation between the expression levels of FBXW7 and c-MYC transcriptional activity was observed.ConclusionsDownregulation of FBXW7 is ubiquitous in human iCCA and cooperates with AKT to induce cholangiocarcinogenesis in mice via c-Myc-dependent mechanisms. Targeting c-MYC might represent an innovative therapy against iCCA exhibiting low FBXW7 expression.Lay summaryThere is mounting evidence that FBXW7 functions as a tumor suppressor in many cancer types, including intrahepatic cholangiocarcinoma, through its ability to promote the degradation of numerous oncoproteins. Herein, we have shown that the low expression of FBXW7 is ubiquitous in human cholangiocarcinoma specimens. This low expression is correlated with increased c-MYC activity, leading to tumorigenesis. Our findings suggest that targeting c-MYC might be an effective treatment for intrahepatic cholangiocarcinoma.
| S-EPMC6773530 | biostudies-literature
Project description:BACKGROUND:Long non-coding RNAs (lncRNAs) have been associated with non-small cell lung cancer (NSCLC), but the underlying molecular mechanisms of their specific roles in mediating aerobic glycolysis have been poorly explored. METHODS:Next-generation RNA sequencing assay was performed to identify the differentially expressed RNAs between NSCLC tissues with high 18F-fluorodeoxyglucose (FDG) uptake and their adjacent normal lung tissues. LINC01123 expression in NSCLC tissues was measured by real-time PCR and in situ hybridization (ISH) assay. The biological role of LINC01123 in cell growth and aerobic glycolysis capability was determined by performing functional experiments in vitro and in vivo. Further, the transcription of LINC01123 was explored by bioinformatics analysis, dual-luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. RNA immunoprecipitation (RIP) and luciferase analyses were used to confirm the predicted competitive endogenous RNA (ceRNA) mechanisms between LINC01123 and c-Myc. RESULTS:Three hundred sixty-four differentially expressed genes were identified in RNA-seq assay, and LINC01123 was one of the most overexpressed lncRNAs. Further validation in expanded NSCLC cohorts confirmed that LINC01123 was upregulated in 92 paired NSCLC tissues and associated with poor survival. Functional assays showed that LINC01123 promoted NSCLC cell proliferation and aerobic glycolysis. Mechanistic investigations revealed that LINC01123 was a direct transcriptional target of c-Myc. Meanwhile, LINC01123 increased c-Myc mRNA expression by sponging miR-199a-5p. In addition, rescue experiments showed that LINC01123 functioned as an oncogene depending on miR-199a-5p and c-Myc. CONCLUSION:Since LINC01123 is upregulated in NSCLC, correlates with prognosis, and controls proliferation and aerobic glycolysis by a positive feedback loop with c-Myc, it is expected to be a potential biomarker and therapeutic target for NSCLC.
| S-EPMC6728969 | biostudies-literature
Project description:Macrophage activation is a key event that triggers inflammatory response. The activation is accompanied by metabolic shift such as upregulated glucose metabolism. There are accumulating evidences showing the anti-inflammatory activity of Momordica charantia. However, the effects of M. charantia on inflammatory response and glucose metabolism in activated macrophages have not been fully established. The present study aimed to examine the effect of M. charantia in modulating lipopolysaccharide (LPS)-induced inflammation and perturbed glucose metabolism in RAW264.7 murine macrophages. The results showed that LPS-induced NF-κB (p65) nuclear translocation was inhibited by M. charantia treatment. In addition, M. charantia was found to reduce the expression of inflammatory genes including IL6, TNF-α, IL1β, COX2, iNOS, and IL10 in LPS-treated macrophages. Furthermore, the data showed that M. charantia reduced the expression of GLUT1 and HK2 genes and lactate production (-28%), resulting in suppression of glycolysis. Notably, its effect on GLUT1 gene expression was found to be independent of LPS-induced inflammation. A further experiment also indicated that the bioactivities of M. charantia may be attributed to its key bioactive compound, charantin. Taken together, the study provided supporting evidences showing the potential of M. charantia for the treatment of inflammatory disorders.
| S-EPMC7504525 | biostudies-literature
Project description:MYC deregulation is a driver of many human cancers. Altering the balance of MYC protein levels at the level of transcription, protein stability, or turnover is sufficient to transform cells to a tumorigenic phenotype. While direct targeting of MYC is difficult, specific genetic vulnerabilities of MYC-deregulated cells could be exploited to selectively inhibit their growth. Using a genome-wide shRNA screen, we identified 78 candidate genes, which are required for survival of human mammary epithelial cells with elevated MYC levels. Among the candidates, we validated and characterized FBXW7, a component of the SCF-like ubiquitin ligase complex that targets MYC for proteasomal degradation. Down-regulation of FBXW7 leads to synergistic accumulation of cellular and active chromatin-bound MYC, while protein levels of other FBXW7 targets appear unaffected. Over a four-week time course, continuous FBXW7 down-regulation and MYC activation together cause an accumulation of cells in S-phase and G2/M-phase of the cell cycle. Under these conditions, we also observe elevated chromatin-bound levels of CDC45, suggesting increased DNA replication stress. Consistent with these results, FBXW7 down-regulation alone decreases the survival of T47D breast cancer cells. These results establish that FBXW7 down-regulation is synthetic lethal with MYC, and that MYC is a critical target of FBXW7 in breast epithelial cells.
| S-EPMC4413654 | biostudies-literature
Project description:The Warburg effect (aerobic glycolysis), a hallmark of cancer, serves as a promising target for diagnosis and therapy. Growing evidence indicates that long non-coding RNAs (lncRNAs) play an important role in aerobic glycolysis of various tumours. However, the correlation between lncRNAs and glycolysis in thyroid cancer cells is still poorly understood. In this study, we showed that lncRNA papillary thyroid cancer susceptibility candidate 3 (PTCSC3) was significantly downregulated in papillary thyroid carcinoma (PTC). Overexpression of PTCSC3 significantly inhibited the aerobic glycolysis and tumour growth of PTC cells. Consistently, PTCSC3 overexpression suppressed tumour progress in vivo. Mechanistically, PTCSC3 inhibits aerobic glycolysis and proliferation of PTC by directly interacting with PGK1, a key enzyme in glycolytic pathway. As a result, PTCSC3 performs its role in PTC development via PGK1 and may be a potential therapeutic target for PTC treatment.
| S-EPMC8419167 | biostudies-literature
Project description:Triple Negative Breast cancer accounts for some of the most aggressive types of breast cancer. By interrogating clinical datasets, we found that the activities of p63 and Hypoxia-Inducible-Factors (HIFs), two master regulators of the invasive and metastatic cancer cell phenotype are linked in TNBC through the p63-target Sharp1. Mechanistically, Sharp1 promotes HIF-1α/HIF-2α proteasomal degradation by serving as HIFs presenting factor to the proteasome independently from oxygen levels and prior ubiquitination. To investigate unbiasedly if Sharp1 is a general inhibitor of HIF induced transcriptional program, we compared the transcriptomic profile of cells either overexpressing Sharp1 or depleted of HIF1a and HIF2a. We collected RNA from control MDA-MB-231 cells (shGFP) or MDA-MB-231 cells overexpressing Sharp1 or MDA-MB-231 cells depleted of HIF1a and HIF2a (shHIF). Cells were left untreated in normal culturing conditions before harvesting. Samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Four biological replicas (A, B, C, D) were used for each of the 4 conditions (1: shGFP, control cells; 2: shHIF cells; 3: Sharp1-overexpressing cells) for a total of 12 samples.
2012-07-18 | E-GEOD-33950 | biostudies-arrayexpress
Project description:c-Myc, a key activator of cell proliferation and angiogenesis, promotes the development and progression of breast cancer. Ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) is a multifunctional scaffold protein that suppresses the proliferation of breast cancer cells. In this study we investigated whether the cancer-suppressing effects of EBP50 resulted from its regulation of c-Myc signaling in human breast cancer MCF-7 cells in vitro and in vivo. We first found a significant correlation between EBP50 and c-Myc expression levels in breast cancer tissue, and demonstrated that EBP50 suppressed cell proliferation through decreasing the expression of c-Myc and its downstream proteins cyclin A, E and Cdc25A in MCF-7 cells. We further showed that EBP50 did not regulate c-Myc mRNA expression, but it promoted the degradation of c-Myc through the autophagic lysosomal pathway. Moreover, EBP50 promoted integration between c-Myc and p62, an autophagic cargo protein, triggering the autophagic lysosomal degradation of c-Myc. In EBP50-silenced MCF-7 cells, activation of autophagy by Beclin-1 promoted the degradation of c-Myc and inhibited cell proliferation. These results demonstrate that the EBP50/Beclin-1/p62/c-Myc signaling pathway plays a role in the proliferation in MCF-7 breast cancer cells: EBP50 stimulates the autophagic lysosomal degradation of c-Myc, thereby inhibits the proliferation of MCF-7 cells. Based on our results, promoting the lysosomal degradation of c-Myc might be a promising new strategy for treating breast cancer.
| S-EPMC6289381 | biostudies-literature