Microtubule depolymerization activates the Epstein–Barr virus lytic cycle through protein kinase C pathways in nasopharyngeal carcinoma cells

Abstract

Elevated levels of antibodies against Epstein-Barr virus (EBV) and the presence of viral DNA in plasma are reliable biomarkers for the diagnosis of nasopharyngeal carcinoma (NPC) in highprevalence areas, such as South-East Asia. The presence of these viral markers in the circulation suggests that a minimal level of virus reactivation may have occurred in an infected individual, although the underlying mechanism of reactivation remains to be elucidated. Here, we showed that treatment with nocodazole, which provokes the depolymerization of microtubules, induces the expression of two EBV lytic cycle proteins, Zta and EA-D, in EBV-positive NPC cells. This effect was independent of mitotic arrest, as viral reactivation was not abolished in cells synchronized at interphase. Notably, the induction of Zta by nocodazole was mediated by transcriptional upregulation via protein kinase C (PKC). Pre-treatment with inhibitors for PKC or its downstream signalling partners p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) abolished the nocodazole-mediated induction of Zta and EA-D. Interestingly, the effect of nocodazole, as well as colchicine and vinblastine, on lytic gene expression occurred only in NPC epithelial cells but not in cells derived from lymphocytes. These results establish a novel role of microtubule integrity in controlling the EBV life cycle through PKC and its downstream pathways, which represents a tissue-specific mechanism for controlling the life-cycle switch of EBV.

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

“…Liu et al . also recently reported that nocodazole, which could induce mitotic arrest in various types of cell lines, could reactivate EBV lytic cycle in NPC cells . The exact relationship of cell cycle arrest and lytic cycle reactivation in EBV‐positive cancer cells deserves further investigation.…”

“…Liu et al also recently reported that nocodazole, which could induce mitotic arrest in various types of cell lines, could reactivate EBV lytic cycle in NPC cells. 39 The exact relationship of cell cycle arrest and lytic cycle reactivation in EBV-positive cancer cells deserves further investigation. To further evaluate the role of HDAC inhibition in the lytic reactivation by HDAC inhibitors, we performed shRNA knockdown experiments to specifically inhibit HDAC-1, -2 and -3.…”

Epstein-Barr virus lytic reactivation regulation and its pathogenic role in carcinogenesis

“…The switch, marked by Zta expression, can be induced by active NF-κB and AP-1 through PKC. This report was followed by similar reports from other groups 36,37. The MAPK family consists of 3 member cascades, extracellular signal regulated kinases (ERKs), c-Jun NH 2 -terminal kinases (JNKs), and p38 and is usually activated as a partner of the PKC signaling pathway.…”

Interplay between cytoskeletal polymerization and the chondrogenic phenotype in chondrocytes passaged in monolayer culture

“…; Liu et al. ). Specifically tubulin and actin filaments are polymers made up of monomeric units and there is evidence that gene expression is actively regulated by the proportion of monomeric to polymeric actin and/or tubulin, raising the possibility that cytoskeletal polymerization status may be important in gene regulation in chondrocytes (Rosette & Karin, ; Hui et al.…”