Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Koguchi,Tomoyuki; Tanikawa,Chizu; Mori,Jinichi; Kojima,Yoshiyuki; Matsuda,Koichi

doi:10.3892/ijo.2016.3456

Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway

Authors:
- Tomoyuki Koguchi
- Chizu Tanikawa
- Jinichi Mori
- Yoshiyuki Kojima
- Koichi Matsuda
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Affiliations: Laboratory of Clinical Sequence, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan, Department of Urology, Fukushima Medical University School of Medicine, Fukushima, Japan
Published online on: March 24, 2016 https://doi.org/10.3892/ijo.2016.3456
Pages: 2415-2424

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Abstract

In response to various cellular stresses, p53 exerts its tumor suppressive effects such as apoptosis, cell cycle arrest, and senescence through the induction of its target genes. Recently, p53 was shown to control cellular homeostasis by regulating energy metabolism, glycolysis, antioxidant effect, and autophagy. However, its function in inositol synthesis was not reported. Through a microarray screening, we found that five genes related with myo-inositol metabolism were induced by p53. DNA damage enhanced intracellular myo-inositol content in HCT116 p53+/+ cells, but not in HCT116 p53-/- cells. We also indicated that inositol 3-phosphate synthase (ISYNA1) which encodes an enzyme essential for myo-inositol biosynthesis as a direct target of p53. Activated p53 regulated ISYNA1 expression through p53 response element in the seventh exon. Ectopic ISYNA1 expression increased myo-inositol levels in the cells and suppressed tumor cell growth. Knockdown of ISYNA1 caused resistance to adriamycin treatment, demonstrating the role of ISYNA1 in p53-mediated growth suppression. Furthermore, ISYNA1 expression was significantly associated with p53 mutation in bladder, breast cancer, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and pancreatic adenocarcinoma. Our findings revealed a novel role of p53 in myo-inositol biosynthesis which could be a potential therapeutic target.

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