Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway
Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway
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DOI：
10.3892/ijo.2016.3456
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发表时间：
2016-06-01
影响因子：
5.2
通讯作者：
Matsuda, Koichi
中科院分区：
文献类型：
--
作者：
Koguchi, Tomoyuki;Tanikawa, Chizu;Matsuda, Koichi
在各种细胞应激反应中，p53通过诱导其靶基因发挥其肿瘤抑制作用，如凋亡、细胞周期阻滞和衰老。最近，p53被证明通过调节能量代谢、糖酵解、抗氧化作用和自噬来控制细胞内稳态。然而，其在肌醇合成中的功能尚未报道。通过基因芯片筛选，我们发现5个肌醇代谢相关基因受p53的诱导。DNA损伤可使HCT 116 p53（+/+）细胞内肌醇含量增加，但对HCT 116 p53（-/-）细胞内肌醇含量无影响。我们还指出，肌醇3-磷酸合酶（ISYNA 1），编码肌醇生物合成所必需的酶作为p53的直接靶点。激活的p53通过第七外显子上的p53反应元件调节ISYNA 1的表达。异位ISYNA 1表达增加细胞中的肌醇水平并抑制肿瘤细胞生长。敲除ISYNA 1导致对阿霉素治疗的抗性，证明了ISYNA 1在p53介导的生长抑制中的作用。此外，ISYNA 1表达与膀胱癌、乳腺癌、头颈部鳞状细胞癌、肺鳞状细胞癌和胰腺癌中的p53突变显著相关。我们的研究结果揭示了p53在肌醇生物合成中的新作用，这可能是一个潜在的治疗靶点。
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.