Abstract
Autophagy, a conserved cellular mechanism, is manipulated by a number of viruses for different purposes. We previously demonstrated that an iron-chelator-like small compound, C7, reactivates Epstein-Barr virus (EBV) lytic cycle by activating the ERK1/2-autophagy axis in epithelial cancers. Here, we aim to identify the specific stage of autophagy required for EBV lytic reactivation, determine the autophagy dependency of EBV lytic inducers including histone deacetylase inhibitor (HDACi) and C7/iron chelators, for EBV lytic reactivation and measure the combinatorial effects of these types of lytic inducers in nasopharyngeal carcinoma (NPC). Inhibition of autophagy initiation by 3-MA and autolysosome formation by chloroquine demonstrated that only autophagy initiation is required for EBV lytic reactivation. Gene knockdown of various autophagic proteins such as beclin-1, ATG5, ATG12, ATG7, LC3B, ATG10, ATG3 and Rab9, revealed the importance of ATG5 in EBV lytic reactivation. 3-MA could only abrogate lytic cycle induction by C7/iron chelators but not by HDACi, providing evidence for autophagy-dependent and independent mechanisms in EBV lytic reactivation. Finally, the combination of C7 and SAHA at their corresponding reactivation kinetics enhanced EBV lytic reactivation. These findings render new insights in the mechanisms of EBV lytic cycle reactivation and stimulate a rational design of combination drug therapy against EBV-associated cancers.
Highlights
Epstein-Barr virus (EBV), a γ-herpesvirus, infects over 90% of the adult human population worldwide and is associated with various cancers, including Burkitt’s lymphoma (BL), Hodgkin disease (HD), nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma (GC), of which NPC is highly prevalent in the regions of Southern China [1,2]
We aim to identify the specific stage of autophagy required for EBV lytic reactivation, determine the autophagy dependency of EBV lytic inducers including histone deacetylase inhibitor (HDACi) and C7/iron chelators, for EBV lytic reactivation and measure the combinatorial effects of these types of lytic inducers in NPC
We have previously reported that C7 and iron chelators reactivate EBV lytic cycle by chelating intracellular iron and activating the ERK1/2-autophagy axis [6]
Summary
Epstein-Barr virus (EBV), a γ-herpesvirus, infects over 90% of the adult human population worldwide and is associated with various cancers, including Burkitt’s lymphoma (BL), Hodgkin disease (HD), nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma (GC), of which NPC is highly prevalent in the regions of Southern China [1,2]. In these associated cancers, EBV remains in its latent form expressing only a few EBV proteins. Given that autophagy is a conserved cellular mechanism for maintaining cellular homeostasis and plays an essential role in governing cell death and survival [7,8,9], we endeavor to further delineate the role of autophagy in EBV lytic reactivation.
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