Hibitors could inhibit a variety of varieties of HDAC enzymes and mediate potent anti-cancer effect inside a wide selection of malignancies [16]. We reported that FDAapproved HDAC inhibitors, like suberoylanilide hydroxamic acid (SAHA) and romidepsin, could induce development arrest and apoptosis of EBV-positive gastric carcinoma and nasopharyngeal carcinoma cells by disrupting EBV latency [179]. HDAC inhibitors could also induce expression of p21WAF1 which was downregulated by EBNA3C [13, 20]. Proteasome inhibitor, like bortezomib, belongs to an emerging class of anti-cancer drugs which induce endoplasmic reticulum (ER) stressrelated cell death via inhibition in the proteasomal degradation of unfolded proteins [21]. We and other people had reported that combination of HDAC and proteasome inhibitors could mediate sturdy synergistic killing of cancer cells through generation of reactive oxygen species (ROS), activation of ER stress and induction of autophagy [215]. Moreover, we found that combination of SAHA and bortezomib (SAHA/bortezomib) could preferentially induce killing of LCLs and BL cells of Wp-restricted latency, both of which express EBNA3A, -3B and -3C proteins [26]. These data suggested the involvement from the EBNA3 protein(s) inside the cell death mechanism mediated by SAHA/bortezomib. Combination of HDAC and proteasome inhibitors was identified to induce DNA harm response (DDR) in numerous tumor cells [27, 28]. In response to DDR, cells were arrested at cell cycle checkpoints so as to offer adequate time for the cells to repair the broken DNA [29]. Ataxia telangiectasia mutated/Rad3-related (ATM/ATR) pathways had been known to mediate G1 arrest via p53/p21 pathway and G2/M arrest by way of inactivation of cdc25c [30, 31]. EBNA3C was shown to release the DDR-induced G2/M arrest by way of dysregulated cdc25c phosphorylation when cells had been exposed to nocodazole [11]. However, the effects of Tebufenozide web mixture of HDAC and proteasome inhibitors on the cell cycle progression and survival of EBNA-3 expressing cells haven’t been investigated. We hypothesize that SAHA/bortezomib can induce synergistic killing of BL and LCLs via targeting the survival functions of EBNA3 proteins. To test this hypothesis, we examined the impact of SAHA/ bortezomib on the survival of BL cell lines which harbor EBNA3A or -3B or -3C knockout EBV with or devoid of the individual revertant. We discovered that EBNA3C played a much more critical function inside the synergistic killing of BL cells and LCLs when compared with EBNA3A and EBNA3B. Our data recommended that SAHA/bortezomib targeted the survival functions of EBNA3C protein in BL and LCLs. That is the initial study to show that mixture of HDAC/ proteasome inhibitors can indeed target latent viral protein function in EBV-associated LPDs.OncotargetRESULTSCombination of HDAC and proteasome inhibitors (i.e. SAHA /bortezomib) synergistically inhibited the proliferation of EBNA3C-expressing BL cellsWe had reported that mixture of HDAC and proteasome inhibitors could induce distinct synergistic killing of EBV-positive BL cells and LCLs which express EBNA3 proteins. To investigate the necessary part of EBNA-3 proteins within the survival of cells, we tested that effects of combination of HDAC and proteasome inhibitors around the proliferation of eight distinctive BL31 cell lines, such as a EBV-negative BL31 cell line (EBV -ve) and BL31 cell lines infected with wild variety EBV (EBV +ve), EBNA-3A-knockout (3A-KO), EBNA-3Bknockout (3B-KO), EBNA-3C-knockout.