Characterization of the human <i>IDH1</i> gene promoter

Yutaka Takihara; Ryuji Otani; Takuro Ishii; Shunsuke Takaoka; Yuki Nakano; Kaori Inoue; Steven Larsen; Yoko Ogino; Masashi Asai; Sei-ichi Tanuma; Fumiaki Uchiumi; Yutaka Takihara; Ryuji Otani; Takuro Ishii; Shunsuke Takaoka; Yuki Nakano; Kaori Inoue; Steven Larsen; Yoko Ogino; Masashi Asai; Sei-ichi Tanuma; Fumiaki Uchiumi

doi:10.3934/molsci.2023013

AIMS Molecular Science

2023, Volume 10, Issue 3: 186-204. doi: 10.3934/molsci.2023013

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Research article

Characterization of the human IDH1 gene promoter

1.
Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba-ken 278-8510, Japan
2.
Department of Kampo Pharmacology, Faculty of Pharmaceutical Sciences, Yokohama University of Pharmacy, Yokohama-Shi, Kanagawa-ken 245-0066, Japan
3.
Genomic Medicinal Science, Research Institute for Science and Technology, Tokyo University of Science, Noda-shi, Chiba-ken 278-8510, Japan

Received: 22 May 2023 Revised: 08 August 2023 Accepted: 18 August 2023 Published: 28 August 2023

In cancer, the production of ATP depends mainly on glycolysis, usually accompanied by the dysfunction of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme for various biological enzymatic reactions such as those involved in the TCA cycle. To investigate the molecular mechanisms involved in carcinogenesis, the transcription system of genes associated with mitochondrial function should be elucidated. In this study, we isolated several mitochondrial function-associated bidirectional promoters and tested whether they responded to NAD⁺-metabolism regulating compounds, namely, trans-resveratrol (Rsv), 2-deoxy-D-glucose (2DG), 3-amino benzamide (3AB), and olaparib (OLA), in HeLa S3 cells. Transient transfection and luciferase (Luc) reporter assay showed that the IDH1 promoter was prominently activated by these compounds. The IDH1 gene, which encodes a nicotinamide adenine dinucleotide phosphate (NADP⁺) dependent isocitrate dehydrogenase, is frequently mutated in glioma and leukemia cells. In this study, RT-PCR showed that IDH1 gene and protein expression was induced in response to the NAD⁺-regulating drugs Rsv and 3AB. However, IDH1 protein amount was rather stable at control level. The result suggested that a post-transcriptional controlling system works to keep IDH1 at a stable level.
- bidirectional promoter,
- ETS,
- GGAA,
- IDH1,
- PARPi,
- resveratrol,
- transcription
Citation: Yutaka Takihara, Ryuji Otani, Takuro Ishii, Shunsuke Takaoka, Yuki Nakano, Kaori Inoue, Steven Larsen, Yoko Ogino, Masashi Asai, Sei-ichi Tanuma, Fumiaki Uchiumi. Characterization of the human IDH1 gene promoter[J]. AIMS Molecular Science, 2023, 10(3): 186-204. doi: 10.3934/molsci.2023013

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Abstract

In cancer, the production of ATP depends mainly on glycolysis, usually accompanied by the dysfunction of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Nicotinamide adenine dinucleotide (NAD⁺) is a coenzyme for various biological enzymatic reactions such as those involved in the TCA cycle. To investigate the molecular mechanisms involved in carcinogenesis, the transcription system of genes associated with mitochondrial function should be elucidated. In this study, we isolated several mitochondrial function-associated bidirectional promoters and tested whether they responded to NAD⁺-metabolism regulating compounds, namely, trans-resveratrol (Rsv), 2-deoxy-D-glucose (2DG), 3-amino benzamide (3AB), and olaparib (OLA), in HeLa S3 cells. Transient transfection and luciferase (Luc) reporter assay showed that the IDH1 promoter was prominently activated by these compounds. The IDH1 gene, which encodes a nicotinamide adenine dinucleotide phosphate (NADP⁺) dependent isocitrate dehydrogenase, is frequently mutated in glioma and leukemia cells. In this study, RT-PCR showed that IDH1 gene and protein expression was induced in response to the NAD⁺-regulating drugs Rsv and 3AB. However, IDH1 protein amount was rather stable at control level. The result suggested that a post-transcriptional controlling system works to keep IDH1 at a stable level.

Acknowledgments

The authors are grateful to Kohei Hoshino, Yuka Iinuma and Yutaka Yamamoto for excellent technical assistance. This study was performed under the permission of the recombinant DNA experimental committee admission No 1754 of the Tokyo University of Science. The present study was supported in part by JSPS KAKENHI grant no. 24510270 and a Research Fellowship from the Research Center for RNA Science, RIST, Tokyo University of Science.

Conflict of interest

Fumiaki Uchiumi is an editorial board member for AIMS Molecular Science and was not involved in the editorial review or the decision to publish this article.
The authors declare that they have no competing interests.

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