LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

Xiang, Shaoxun; Gu, Hao; Jin, Lei; Thorne, Rick F.; Zhang, Xu Dong; Wu, Mian

doi:10.1073/pnas.1711257115

Cited by 98 publications

(76 citation statements)

References 68 publications

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“…Of note, c-Myc is also a key transcription factor that regulates gene expression via directly binding to the E-box motif on the promoter [26]. Many genes have been identified as the downstream targets of c-Myc, including lncRNAs, such as MINCR [27] and IDH1-AS1 [28]. In the present study, we found three E-box motifs on linc02042 promoter, thus speculated that linc02042 might be also regulated by c-Myc.…”

Section: Discussionsupporting

confidence: 57%

A novel positive feedback loop of linc02042 and c-Myc mediated by YBX1 promotes tumorigenesis and metastasis in esophageal squamous cell carcinoma

Zhang

Qiu

et al. 2020

Cancer Cell Int

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Background: Long non-coding RNA (lncRNA) is a class of endogenous RNA with a length of more than 200 nucleotides, which is emerging as a pivotal player in cancer development and progression. However, the functional roles of many members in this class remain largely uncharacterized. In the present study, we explored the biological relevance of linc02042 in esophageal squamous cell carcinoma (ESCC). Methods: qRT-PCR was used to detect the levels of linc02042 and c-Myc. Western blot was used to assess protein expression level. CCK-8 and Transwell assays were employed to test ESCC cell proliferation and invasion, respectively. The mice study including xenograft tumor and lung metastasis models was used to determine the role of linc02042 in vivo. RNA pull-down, ChIP and luciferase reporter assays were employed to test the relationship between linc02042, YBX1 and c-Myc. Results: Linc02042 was found to be markedly upregulated in ESCC cell lines, tissues and plasma, and was closely correlated with malignant clinical features. Knockdown of linc02042 significantly inhibited ESCC cell viability and invasion in vitro as well as tumor growth and lung metastasis in vivo, whereas overexpression of linc02042 resulted in the opposite results. Mechanistically, linc02042 acted as a scaffold for YBX-1 binding to the 3′-UTR of c-Myc mRNA, leading to enhanced c-Myc mRNA stability, thereby facilitating ESCC growth and metastasis. Moreover, in turn, c-Myc was able to transcriptionally elevate linc02042 by directly binding to the E-box motif proximal to the transcription start site (TSS) of linc02042 promoter. Clinically, linc02042 was identified as an effective diagnostic and prognostic biomarker for ESCC patients, and its expression was strongly positively correlated with c-Myc expression in ESCC tissues. Conclusion: Our data suggest that linc02042 plays an important tumor-promoting role in ESCC, which lays a foundation for considering it as a potential target for ESCC patients.

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Section: Discussionsupporting

confidence: 57%

A novel positive feedback loop of linc02042 and c-Myc mediated by YBX1 promotes tumorigenesis and metastasis in esophageal squamous cell carcinoma

Zhang

Qiu

et al. 2020

Cancer Cell Int

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“…It has been demonstrated that most cancer cells have altered energy metabolism characterized by glycolysis with lactate production and a higher uptake of glucose as the main source of energy even in the presence of oxygen, well-known as the "Warburg effect" (11,12). Under normoxic conditions, glycolysis is commonly driven by c-Myc (13,14), which upregulates glycolytic enzymes such as lactate dehydrogenase A (LDHA) and hexokinase 2 (HK2) (15)(16)(17). Many non-coding RNAs have been reported to be involved in the regulation of cancer metabolism (18).…”

Section: Introductionmentioning

confidence: 99%

Long Non-coding RNA MEG3 Activated by Vitamin D Suppresses Glycolysis in Colorectal Cancer via Promoting c-Myc Degradation

Zuo

Wang

et al. 2020

Front. Oncol.

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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) 2 D 3 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.

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“…The Warburg effect is controlled by key glycolytic enzymes including hexokinase (HK), phosphofructokinase (PFK), pyruvate kinase (PK), and lactate dehydrogenase (LDH) [8]. Lately, long non-coding RNAs have been identified as a class of crucial regulators of the Warburg effect [9,10]. However, the detailed lncRNA regulatory network modulated by 20(S)-Rg3 to prevent the Warburg effect in ovarian cancer cells has not been fully explored.…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside 20(S)-Rg3 Prevents PKM2-Targeting miR-324-5p from H19 Sponging to Antagonize the Warburg Effect in Ovarian Cancer Cells

Zheng

Zhou

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: The Warburg effect is one of the main metabolic features for cancers, with long non-coding RNA (lncRNA) being involved as a class of crucial regulators. Our previous studies have shown that ginsenoside 20(S)-Rg3, an active saponin monomer extracted from red ginseng, inhibits the Warburg effect in ovarian cancer cells. However, the detailed lncRNA regulatory network modulated by 20(S)-Rg3 to prevent the Warburg effect in ovarian cancer cells has not been explored. Methods: High-throughput sequencing was used to screen out the differentially expressed lncRNAs between 20(S)-Rg3-treated and non-treated SKOV3 cells. The levels of lncRNA H19 and miR-324-5p were manipulated in SKOV3 and A2780, and the glucose consumption, lactate production and PKM2 protein level were detected. Dual-luciferase reporter assay and RIP were utilized to verify the direct binding of H19 to miR-324-5p and miR-324-5p to PKM2. Cell proliferation was examined by CCK8 and colony formation assay. Nude mice subcutaneous xenograft tumor models were established to evaluate the impact of miR-324-5p on tumor growth in vivo. Results: 20(S)-Rg3 downregulated 67 lncRNAs, and H19 was one of the most decreased lncRNAs. Suppression of H19 by siRNA transfection reduced glucose consumption, lactate production and PKM2 expression in ovarian cancer cells, while H19 overexpression in 20(S)-Rg3-treated ovarian cancer cells enhanced glucose consumption, lactate production and PKM2 expression. Dual-luciferase reporter assay and RIP results showed that H19 directly bound to miR-324-5p. Dual-luciferase reporter assay showed that miR-324-5p directly targeted PKM2, and miR-324-5p negatively regulated glucose consumption and lactate production in ovarian cancer cells. miR-324-5p overexpression inhibited cell proliferation in vitro and in vivo. Conclusion: Our study revealed that 20(S)-Rg3 blocked the competitive inhibition of H19 on miR-324-5p, which enhanced the suppression of miR-324-5p on PKM2 and therefore inhibited the Warburg effect and repressed tumorigenesis. In a word, 20(S)-Rg3 inhibited the Warburg effect in ovarian cancer cells via H19/miR-324-5p/PKM2 pathway.

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LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

Cited by 98 publications

References 68 publications

A novel positive feedback loop of linc02042 and c-Myc mediated by YBX1 promotes tumorigenesis and metastasis in esophageal squamous cell carcinoma

A novel positive feedback loop of linc02042 and c-Myc mediated by YBX1 promotes tumorigenesis and metastasis in esophageal squamous cell carcinoma

Long Non-coding RNA MEG3 Activated by Vitamin D Suppresses Glycolysis in Colorectal Cancer via Promoting c-Myc Degradation

Ginsenoside 20(S)-Rg3 Prevents PKM2-Targeting miR-324-5p from H19 Sponging to Antagonize the Warburg Effect in Ovarian Cancer Cells

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