Li Yifan, Wang Lei, Ai Weipeng, He Nianhui, Zhang Lin, Du Jihui, Wang Yong, Mao Xingjian, Ren Junqi, Xu Dan, Zhou Bei, Li Rong, Mai Liwen
Central Laboratory, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518052, P.R. China.
Department of Clinical Pharmacology, Shenzhen Nanshan People's Hospital/Affiliated Shenzhen Sixth Hospital of Guangdong Medical University, Shenzhen, Guangdong 518052, P.R. China.
Int J Mol Med. 2017 Sep;40(3):661-672. doi: 10.3892/ijmm.2017.3051. Epub 2017 Jul 3.
All-trans retinoic acid (atRA), which is mainly generated endogenously via two steps of oxidation from vitamin A (retinol), plays an indispensible role in the development of the kidney and many other organs. Enzymes that catalyze the oxidation of retinol to generate atRA, including aldehyde dehydrogenase 1 family (ALDH1)A1, ALDH1A2 and ALDH1A3, exhibit complex expression patterns at different stages of renal development. However, molecular triggers that control these differential expression levels are poorly understood. In this study, we provide in vitro evidence to demonstrate that Wilms' tumor 1 (WT1) negatively regulates the expression of the atRA synthetic enzymes, ALDH1A1, ALDH1A2 and ALDH1A3, in the 293 cell line, leading to significant blockage of atRA production. Furthermore, we demonstrate that the suppression of ALDH1A1 by WT1 can be markedly attenuated by histone deacetylase inhibitors (HDACis). Taken together, we provide evidence to indicate that WT1 and HDACs are strong regulators of endogenous retinoic acid synthetic enzymes in 293 cells, indicating that they may be involved in the regulation of atRA synthesis.
全反式维甲酸（atRA）主要通过维生素A（视黄醇）的两步氧化内源性生成，在肾脏和许多其他器官的发育中发挥着不可或缺的作用。催化视黄醇氧化生成atRA的酶，包括醛脱氢酶1家族（ALDH1）A1、ALDH1A2和ALDH1A3，在肾脏发育的不同阶段表现出复杂的表达模式。然而，控制这些差异表达水平的分子触发因素却知之甚少。在本研究中，我们提供了体外证据，证明威尔姆斯瘤1（WT1）在293细胞系中负调控atRA合成酶ALDH1A1、ALDH1A2和ALDH1A3的表达，导致atRA生成显著受阻。此外，我们证明组蛋白去乙酰化酶抑制剂（HDACis）可明显减弱WT1对ALDH1A1的抑制作用。综上所述，我们提供的证据表明WT1和HDACs是293细胞内源性视黄酸合成酶的强调节因子，表明它们可能参与atRA合成的调控。
