Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, Hefei 230031, China; University of Science and Technology of China, Hefei 230026, China.
Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Chinese Academy of Sciences, Hefei 230031, China.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118541. doi: 10.1016/j.bbamcr.2019.118541. Epub 2019 Aug 29.
Jumonji C (JmjC) domain-containing proteins have been shown to regulate cellular processes by hydroxylating or demethylating histone and non-histone targets. JMJD8 is a Jumonji C domain-containing protein localized in the lumen of the endoplasmic reticulum and was recently shown to be involved in endothelial differentiation and cellular inflammation response. However, other physiological functions of JMJD8 remain to be elucidated. In this research, we found that knockdown of JMJD8 in cancer cells significantly increased cell proliferation, and attenuated ionizing irradiation or etoposide treatment-induced DNA double-strand breaks (DSBs) level through enhancing the expression of Ku70 and Ku80 which are key participants in the non-homologous end-joining repair of DSBs. We also provided evidence to show that knockdown of JMJD8 up-regulated cyclooxygenase-2 (COX-2) expression which contributed to the enhanced expression of Ku70/Ku80 as shown by the results that pre-treatment of JMJD8 knockdown cells with COX-2 selective inhibitor NS-398 inhibited the induction of Ku70/Ku80. Furthermore, we identified that the up-regulation of COX-2 in JMJD8 knockdown cells was partially due to the increased activation of AKT/NF-κB signaling, and LY294002 (an inhibitor of the PI3K/AKT signaling pathway) repressed the induction of COX-2 and Ku70/Ku80. In conclusion, our research provided data to establish the role of JMJD8 in regulating tumor cell proliferation and their sensitivity to ionizing irradiation or chemo-therapy drug, and the AKT/NF-κB/COX-2 signaling mediated expression of Ku70/Ku80 was involved. The results of this research indicated that JMJD8 is a potential target for enhancing the efficacy of tumor radio- and chemo-therapies.
Jumonji C (JmjC) 结构域蛋白已被证明通过羟基化或去甲基化组蛋白和非组蛋白靶标来调节细胞过程。JMJD8 是一种含有 JmjC 结构域的蛋白，位于内质网腔中，最近被证明参与内皮细胞分化和细胞炎症反应。然而，JMJD8 的其他生理功能仍有待阐明。在这项研究中，我们发现癌细胞中 JMJD8 的敲低显著增加了细胞增殖，并通过增强 Ku70 和 Ku80 的表达来减弱电离辐射或依托泊苷处理诱导的 DNA 双链断裂 (DSBs) 水平，Ku70 和 Ku80 是 DSBs 非同源末端连接修复的关键参与者。我们还提供了证据表明，JMJD8 的敲低上调了环氧化酶-2 (COX-2) 的表达，这导致 Ku70/Ku80 的表达增强，如 JMJD8 敲低细胞用 COX-2 选择性抑制剂 NS-398 预处理抑制 Ku70/Ku80 的诱导所示。此外，我们发现 JMJD8 敲低细胞中 COX-2 的上调部分是由于 AKT/NF-κB 信号通路的激活增加，而 LY294002（PI3K/AKT 信号通路的抑制剂）抑制了 COX-2 和 Ku70/Ku80 的诱导。总之，我们的研究提供了数据，证明了 JMJD8 在调节肿瘤细胞增殖及其对电离辐射或化疗药物的敏感性中的作用，并且 AKT/NF-κB/COX-2 信号通路介导的 Ku70/Ku80 的表达参与其中。这项研究的结果表明，JMJD8 是增强肿瘤放化疗疗效的潜在靶点。
