Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, People's Republic of China.
Department of Anorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, People's Republic of China.
Int J Nanomedicine. 2020 Mar 5;15:1457-1468. doi: 10.2147/IJN.S228839. eCollection 2020.
Zinc oxide nanoparticles (nZnO) have been widely used in the medicine field. Numerous mechanistic studies for nZnO's anticancer effects are merely performed under high concentration exposure. However, possible anticancer mechanisms of epigenetic dysregulation induced by low doses of nZnO are unclear.
nZnO were characterized and bladder cancer T24 cells were treated with nZnO for 48 hrs at different exposure concentrations. Cell cycle, apoptosis, cell migration and invasion were determined. We performed qRT-PCR, Western blot and chromatin immunoprecipitation to detect the mRNA and protein levels of signaling pathway cascades for histone modification.
In this study, we investigated the potential anticancer effects and mechanisms of nZnO on histone modifications in bladder cancer T24 cells upon low-dose exposure. Our findings showed that low concentrations of nZnO resulted in cell cycle arrest at S phase, facilitated cellular late apoptosis, repressed cell invasion and migration after 48 hrs exposure. These anticancer effects could be attributed to increased RUNX3 levels resulting from reduced H3K27me occupancy on the RUNX3 promoter, as well as decreased contents of histone methyltransferase EZH2 and the trimethylation of histone H3K27. Our findings reveal that nZnO are able to enter into the cytoplasm and nucleus of T24 cells. Additionally, both particles and ions from nZnO may jointly contribute to the alteration of histone methylation. Moreover, sublethal nZnO-conducted anticancer effects and epigenetic mechanisms were not associated with oxidative stress or DNA damage.
We reveal a novel epigenetic mechanism for anticancer effects of nZnO in bladder cancer cells under low-dose exposure. This study will provide experimental basis for the toxicology and cancer therapy of nanomaterials.
氧化锌纳米粒子（nZnO）已广泛应用于医学领域。大量关于 nZnO 抗癌作用的机制研究仅在高浓度暴露下进行。然而，低剂量 nZnO 诱导的表观遗传失调的可能抗癌机制尚不清楚。
对 nZnO 进行了表征，并在不同暴露浓度下用 nZnO 处理膀胱癌 T24 细胞 48 小时。检测细胞周期、细胞凋亡、细胞迁移和侵袭。我们进行了 qRT-PCR、Western blot 和染色质免疫沉淀，以检测组蛋白修饰信号通路级联的 mRNA 和蛋白水平。
在这项研究中，我们研究了 nZnO 在低剂量暴露于膀胱癌 T24 细胞时对组蛋白修饰的潜在抗癌作用和机制。我们的研究结果表明，低浓度的 nZnO 导致细胞周期在 S 期停滞，促进细胞晚期凋亡，在 48 小时暴露后抑制细胞侵袭和迁移。这些抗癌作用可能归因于 RUNX3 水平的增加，这是由于 RUNX3 启动子上 H3K27me 占有率降低所致，同时还降低了组蛋白甲基转移酶 EZH2 的含量和组蛋白 H3K27 的三甲基化。我们的研究结果表明，nZnO 能够进入 T24 细胞的细胞质和细胞核。此外，nZnO 的颗粒和离子可能共同导致组蛋白甲基化的改变。此外，低剂量 nZnO 介导的抗癌作用和表观遗传机制与氧化应激或 DNA 损伤无关。
我们揭示了低剂量暴露下 nZnO 在膀胱癌细胞中抗癌作用的一种新的表观遗传机制。本研究将为纳米材料的毒理学和癌症治疗提供实验基础。
