Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis

Zeng, Lihua; Morinibu, Akiyo; Kobayashi, Minoru; Zhu, Yubing; Wang, Xiaosheng; Gotö, Yökö; Yeom, Chan Joo; Zhao, Tao; Hirota, Kiichi; Shinomiya, Kazumi; Itasaka, Satoshi; Yoshimura, Masataka; Guo, Geng; Hammond, Ester M.; Hiraoka, Masahiro; Harada, Hiroshi

doi:10.1038/onc.2014.411

Cited by 87 publications

(121 citation statements)

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“…Identification of a critical regulatory step for the PER 2‐mediated activation of HIF ‐1. (A) After being transiently cotransfected with the HIF ‐1α promoter‐luc reporter gene ( pHIF ‐1α promoter‐luc plasmid ), pRL / TK as an internal control, and either pc DNA 4/ PER 2 ( PER 2) or pc DNA 4/ myc ‐His A ( EV ), HeLa cells were cultured under normoxic or hypoxic conditions, and subjected to the dual luciferase assay and western blotting using the indicated antibodies. (B) After being transiently transfected with either pc DNA 4/ PER 2 ( PER 2) or pc DNA 4/ myc ‐His A ( EV ), HeLa cells were cultured under normoxic or hypoxic conditions, and subjected to qRT ‐ PCR to quantitate the mRNA levels of HIF ‐1α and western blotting using the indicated antibodies.…”

Section: Resultsmentioning

confidence: 99%

“…(B) After being transiently transfected with either pc DNA 4/ PER 2 ( PER 2) or pc DNA 4/ myc ‐His A ( EV ), HeLa cells were cultured under normoxic or hypoxic conditions, and subjected to qRT ‐ PCR to quantitate the mRNA levels of HIF ‐1α and western blotting using the indicated antibodies. (C) After being transiently cotransfected with the HIF ‐1α‐5′ UTR ‐luc reporter gene ( pGL 3/ HIF ‐1α5ʹ UTR ‐luc plasmid ), pRL / TK as an internal control, and either pc DNA 4/ PER 2‐ myc ‐His ( PER 2) or pc DNA 4/ myc ‐His A ( EV ), HeLa cells were cultured under normoxic or hypoxic conditions, and subjected to the dual luciferase assay and western blotting using the indicated antibodies. (D) After being transiently cotransfected with the SV 40p‐ HIF ‐1α ODD (548–603 a.a.)‐luc reporter gene ( pGL 3/ ODD ‐Luc plasmid (39)), pRL / TK as an internal control, and either pc DNA 4/ PER 2 ( PER 2) or pc DNA 4/ myc ‐His A ( EV ), HeLa cells were cultured under normoxic or hypoxic conditions, and then subjected to the dual luciferase assay and western blotting using the indicated antibodies.…”

Section: Resultsmentioning

confidence: 99%

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A circadian clock gene, PER2, activates HIF‐1 as an effector molecule for recruitment of HIF‐1α to promoter regions of its downstream genes

et al. 2017

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Hypoxia-inducible factor 1 (HIF-1) is a transcription factor functioning in cellular adaptive responses to hypoxia. Recent studies have suggested that HIF-1 activity is upregulated by one of the important circadian clock genes, period circadian clock 2 (PER2); however, its underlying mechanism remains unclear. Here, we show that PER2 functions as an effector protein for the recruitment of HIF-1a to its cognate enhancer sequence, the hypoxia-response element (HRE). We found that the forced expression of PER2 enhanced HIF-1 activity without influencing expression levels of the regulatory subunit of HIF-1, HIF-1a, at either mRNA or protein levels. A series of coimmunoprecipitation-based experiments revealed that PER2 interacted with HIF-1a and facilitated the recruitment of HIF-1a to HRE derived from vascular endothelial growth factor (VEGF) promoter. The PER2-mediated activation of HIF-1 was observed only when the asparagine residue at position 803 of HIF-1a (HIF-1a N803) was kept unhydroxylated by hypoxic stimulation, by introducing an N803A point mutation, or by an inhibitor of N803-dioxygenase, deferoxamine. However, the extent of PER-2-HIF-1a interaction was equivalent regardless of the N803 hydroxylation status. Taken together, these results suggest that, with the help of an unknown sensor molecule for the N803 hydroxylation status, PER2 functions as an effector molecule for the recruitment of HIF-1 to promoter regions of its downstream genes. Our findings reveal a novel regulatory step in the activation of HIF-1, which can be targeted to develop therapeutic strategies against HIF-1-related diseases, such as cancers.Abbreviations 5 0 -UTR, 5 0 untranslated region; a.a., amino acid; CBP, CREB-binding protein; CDS, coding sequence; DFO, deferoxamine; FIH-1, factorinhibiting HIF-1; Gal4 DBD, Gal4 DNA-binding domain; HDAC, histone deacetylase; HIF-1, hypoxia-inducible factor 1; HRE, hypoxia-response element; IDH3, isocitrate dehydrogenase 3; LY6E, lymphocyte antigen 6 complex, locus E; mTOR, mammalian target of rapamycin; ODD, oxygen-dependent degradation domain; PER2, period circadian clock 2; PHDs, prolyl-4-hydroxylases; PI3K, phosphatidylinositol 3 kinase; PKC, protein kinase C; pVHL, VHL protein; qRT-PCR, quantitative real-time reverse transcriptase PCR; TAD, transactivation domain; UCHL1, ubiquitin C-terminal hydrolase L1; VEGF, vascular endothelial growth factor; VHL, von-Hippel Lindau.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A circadian clock gene, PER2, activates HIF‐1 as an effector molecule for recruitment of HIF‐1α to promoter regions of its downstream genes

et al. 2017

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“…One prominent example is in the field of cancer research. The mRNA expression levels of IDH3α and VEGF-A were used and visualized as main indicators in 10 major groups of normal tissues 21 in conjunction with the calculated prognostic values by the PrognoScan database 22 . Another example is a study of murine colon proteomes in which colon-specific genes in the mouse version of RefEx were compared to a list of genes from murine colon proteomes that was generated by the researchers’ own results 23 .…”

Section: Discussionmentioning

confidence: 99%

RefEx, a reference gene expression dataset as a web tool for the functional analysis of genes

et al. 2017

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Gene expression data are exponentially accumulating; thus, the functional annotation of such sequence data from metadata is urgently required. However, life scientists have difficulty utilizing the available data due to its sheer magnitude and complicated access. We have developed a web tool for browsing reference gene expression pattern of mammalian tissues and cell lines measured using different methods, which should facilitate the reuse of the precious data archived in several public databases. The web tool is called Reference Expression dataset (RefEx), and RefEx allows users to search by the gene name, various types of IDs, chromosomal regions in genetic maps, gene family based on InterPro, gene expression patterns, or biological categories based on Gene Ontology. RefEx also provides information about genes with tissue-specific expression, and the relative gene expression values are shown as choropleth maps on 3D human body images from BodyParts3D. Combined with the newly incorporated Functional Annotation of Mammals (FANTOM) dataset, RefEx provides insight regarding the functional interpretation of unfamiliar genes. RefEx is publicly available at http://refex.dbcls.jp/.

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“…In this study, there was a synergistic interaction effect of the three treatments on decreasing MVD in Hep-2 and Tu212 xenografts. Some studies have shown that downregulation of HIF-1α alone decreased intratumoral MVD [37, 38]. However, others have found that HIF-1α and GLUT-1 were not correlated with MVD in patients with locally advanced cervical cancer [39].…”

Section: Discussionmentioning

confidence: 99%

In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18F-FDG PET/CT

et al. 2017

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PurposeHypoxia-inducible factor 1α (HIF-1α) and glucose transporter-1 (GLUT-1) are two important hypoxic markers associated with the radioresistance of cancers including laryngeal carcinoma. We evaluated whether the simultaneous inhibition of GLUT-1 and HIF-1α expression improved the radiosensitivity of laryngeal carcinoma. We explored whether the expression of HIF-1α and GLUT-1 was correlated with 2′-deoxy-2’-[18F]fluoro-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography-computed tomography (PET/CT) was appropriate for early evaluation of the response of laryngeal carcinoma to targeted treatment in vivo.Materials and MethodsTo verify the above hypotheses, an in vivo model was applied by subcutaneously injecting Hep-2 (2 × 107/mL × 0.2 mL) and Tu212 cells (2 × 107/mL × 0.2 mL) into nude mice. The effects of HIF-1α antisense oligodeoxynucleotides (AS-ODNs) (100 μg) and GLUT-1 AS-ODNs (100 μg) on the radiosensitivity of laryngeal carcinoma were assessed by tumor volume and weight, microvessel density (MVD), apoptosis index (AI) and necrosis in vivo based on a full factorial (23) design. 18F-FDG-PET/CT was taken before and after the treatment of xenografts. The relationships between HIF-1α and GLUT-1 expression and 18F-FDG uptake in xenografts were estimated and the value of 18F-FDG-PET/CT was assessed after treating the xenografts.Results10 Gy X-ray irradiation decreased the weight of Hep-2 xenografts 8 and 12 days after treatment, and the weights of Tu212 xenografts 8 days after treatment. GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts 12 days after treatment. There was a synergistic interaction among the three treatments (GLUT-1 AS-ODNs, HIF-1α AS-ODNs and 10Gy X-ray irradiation) in increasing apoptosis, decreasing MVD, and increasing necrosis in Hep-2 xenografts 8 days after treatment (p < 0.05) and in Tu212 xenografts 12 days after treatment (p < 0.001). Standardized uptake value (tumor/normal tissue)( SUVmaxT/N) did not show a statistically significant correlation with GLUT1 and HIF-1α expression and therapeutic effect (necrosis, apoptosis).ConclusionsSimultaneous inhibition of HIF-1α and GLUT-1 expression might increase the radiosensitivity of laryngeal carcinoma, decreasing MVD, and promoting apoptosis and necrosis. 18F-FDG-PET/CT wasn't useful in evaluating the therapeutic effect on laryngeal cancer in this animal study.

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Aberrant IDH3α expression promotes malignant tumor growth by inducing HIF-1-mediated metabolic reprogramming and angiogenesis

Cited by 87 publications

References 31 publications

A circadian clock gene, PER2, activates HIF‐1 as an effector molecule for recruitment of HIF‐1α to promoter regions of its downstream genes

A circadian clock gene, PER2, activates HIF‐1 as an effector molecule for recruitment of HIF‐1α to promoter regions of its downstream genes

RefEx, a reference gene expression dataset as a web tool for the functional analysis of genes

In vivo evaluation of the effects of simultaneous inhibition of GLUT-1 and HIF-1α by antisense oligodeoxynucleotides on the radiosensitivity of laryngeal carcinoma using micro 18F-FDG PET/CT

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