Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells.
Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells.
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DOI：
10.1021/acs.chemrestox.7b00248
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发表时间：
2018-02-19
影响因子：
4.1
通讯作者：
Kong AN
中科院分区：
文献类型：
--
作者：
Li W;Su ZY;Guo Y;Zhang C;Wu R;Gao L;Zheng X;Du ZY;Zhang K;Kong AN
TRAMP模型中前列腺癌（PCa）的发生与Nrf 2基因启动子区的高甲基化以及伴随的Nrf 2及其调控的解毒基因的转录降低高度相关。我们旨在研究（3E，5E）-3，5-双（3，4，5-三甲氧基苯亚甲基）-四氢噻喃-4-酮（F10）和（3E，5E）-3，5-双（3，4，5-三甲氧基苯亚甲基）-四氢吡喃-4-酮（E10）这两种合成姜黄素衍生物对TRAMP C1细胞中Nrf 2活性恢复的作用。用F10、E10、姜黄素和萝卜硫素（SFN）处理转染了抗氧化反应元件（ARE）-荧光素酶载体的HepG 2-C8细胞，以比较它们对Nrf 2-ARE通路的影响。我们采用实时荧光定量PCR和蛋白质印迹技术研究了F10和E10对Nrf 2相关II期解毒基因的影响。我们还测量了DNMT和HDAC酶的表达和活性。用染色质免疫沉淀（ChIP）测定探索H3 K27 me 3在Nrf 2的启动子区域上的富集。采用亚硫酸氢盐基因组测序（BGS）和甲基化DNA免疫沉淀（MeDIP）双重检测Nrf 2启动子CpG区的甲基化。与姜黄素和SFN相比，F10在激活Nrf 2-ARE通路方面更有效。F10和E10均提高了Nrf 2和相关II相解毒基因的水平。BGS和MeDIP分析表明，F10而不是E10使Nrf 2启动子低甲基化。F10还下调DNMT 1、DNMT 3a、DNMT 3b、HDAC 1、HDAC 4和HDAC 7的蛋白水平以及DNMT和HDAC的活性。F10而不是E10有效地减少了H3 k27 me 3在Nrf 2启动子上的积累。F10和E10可以激活Nrf 2-ARE途径，提高Nrf 2和相关II相解毒基因的水平。F10对TRAMP C1中Nrf 2的再激活作用可能是通过去甲基化、减少HDAC和抑制H3 k27 me 3积累来实现的。
The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-Bis(3,4,5-trimethoxybenzylidene) - tetrahydrothiopyran-4-one (F10) and (3E,5E)-3,5-Bis(3,4,5-trimethoxybenzylidene) -tetrahydropyran-4- one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed Real-time quantitative PCR and western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter were doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 are more potent in activating Nrf2-ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs and inhibition of H3k27me3 accumulation.
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影响因子：
2
作者：
Jung, Inkyung;Kim, Dongsup
通讯作者：
Kim, Dongsup
影响因子：
4.5
作者：
Wu, Tien-Yuan;Khor, Tin Oo;Kong, Ah-Ng Tony
通讯作者：
Kong, Ah-Ng Tony
影响因子：
3.9
作者：
Edwards JR;Yarychkivska O;Boulard M;Bestor TH
通讯作者：
Bestor TH
影响因子：
3.8
作者：
Ngollo M;Lebert A;Daures M;Judes G;Rifai K;Dubois L;Kemeny JL;Penault-Llorca F;Bignon YJ;Guy L;Bernard-Gallon D
通讯作者：
Bernard-Gallon D
影响因子：
16.8
作者：
Brykczynska, Urszula;Hisano, Mizue;Peters, Antoine H. F. M.
通讯作者：
Peters, Antoine H. F. M.