Marzioni Daniela, Mazzucchelli Roberta, Fantone Sonia, Tossetta Giovanni
Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, 60126, Ancona, Italy.
Department of Biomedical Sciences and Public Health, Section of Pathological Anatomy, School of Medicine, United Hospitals, Università Politecnica Delle Marche, Ancona, Italy.
Mol Biol Rep. 2023 Jan;50(1):873-881. doi: 10.1007/s11033-022-08052-2. Epub 2022 Nov 6.
Prostate cancer (PCa) is one of the most common cancers worldwide and oxidative stress is involved in its occurrence, development and progression. In fact, in transgenic adenocarcinoma of mouse prostate (TRAMP) mice, prostate cancer onset is associated with the methylation of the first five CpG in the nuclear factor erythroid 2-related factor 2 (NRF2) promoter, a key regulator of oxidative stress response, leading to its downregulation and accumulation of reactive oxygen species (ROS). It has been demonstrated that both natural and synthetic compounds can reactivate NRF2 expression inhibiting the methylation status of its promoter by downregulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Interestingly, NRF2 re-expression significantly reduced prostate cancer onset in TRAMP mice highlighting an important role of NRF2 in prostate tumorigenesis.
We analysed the current literature regarding the role of natural and synthetic compounds in modulating NRF2 pathway in TRAMP mice, an in vivo model of prostate cancer, to give an overview on prostate carcinogenesis and its possible prevention.
We can conclude that specific natural and synthetic compounds can downregulate DNMTs and/or HDACs inhibiting the methylation status of NRF2 promoter, then reactivating the expression of NRF2 protecting normal prostatic cells from ROS damage and tumorigenesis.
前列腺癌（PCa）是全球最常见的癌症之一，氧化应激参与其发生、发展和进展过程。事实上，在转基因小鼠前列腺腺癌（TRAMP）小鼠中，前列腺癌的发生与氧化应激反应的关键调节因子核因子红细胞2相关因子2（NRF2）启动子中前五个CpG的甲基化有关，导致其下调和活性氧（ROS）的积累。已经证明，天然和合成化合物都可以通过下调DNA甲基转移酶（DNMTs）和组蛋白脱乙酰酶（HDACs）来抑制NRF2启动子的甲基化状态，从而重新激活NRF2的表达。有趣的是，NRF2的重新表达显著降低了TRAMP小鼠前列腺癌的发生率，突出了NRF2在前列腺肿瘤发生中的重要作用。
我们分析了当前关于天然和合成化合物在调节TRAMP小鼠（一种前列腺癌体内模型）中NRF2通路作用的文献，以概述前列腺癌发生及其可能的预防方法。
我们可以得出结论，特定的天然和合成化合物可以下调DNMTs和/或HDACs，抑制NRF2启动子的甲基化状态，进而重新激活NRF2的表达，保护正常前列腺细胞免受ROS损伤和肿瘤发生。
