JmjC domain-containing protein 8 (JMJD8) represses Ku70/Ku80 expression via attenuating AKT/NF-κB/COX-2 signaling

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.