Inhibition of KAP1 enhances hypoxia-induced Kaposi's sarcoma-associated herpesvirus reactivation through RBP-JÎº.

[primary effusion lymphoma]

Hypoxia-inducible factor 1 Î± (HIF-1 Î±) has been frequently implicated in many cancers as well as viral pathogenesis . Kaposi 's sarcoma -associated herpesvirus (KSHV ) is linked to several human malignancies . It can stabilize HIF-1 Î± during latent infection and undergoes lytic replication in response to hypoxic stress . However , the mechanism by which KSHV controls its latent and lytic life cycle through the deregulation of HIF-1 Î± is not fully understood . Our previous studies showed that the hypoxia-sensitive chromatin remodeler KAP 1 was targeted by the KSHV-encoded latency-associated nuclear antigen (LANA ) to repress expression of the major lytic replication and transcriptional activator (RTA ). Here we further report that an RNA interference-based knockdown of KAP 1 in KSHV-infected primary effusion lymphoma (PEL ) cells disrupted viral episome stability and abrogated sub-G 1 /G 1 arrest of the cell cycle while increasing the efficiency of KSHV lytic reactivation by hypoxia or using the chemical 12 -O-tetradecanoylphorbol-13 -acetate (TPA ) or sodium butyrate (NaB ). Moreover , KSHV genome-wide screening revealed that four hypoxia-responsive clusters have a high concurrence of both RBP-J Îº and HIF-1 Î± binding sites (RBS +HRE ) within the same gene promoter and are tightly associated with KAP 1 . Inhibition of KAP 1 greatly enhanced the association of RBP-J Îº with the HIF-1 Î± complex for driving RTA expression not only in normoxia but also in hypoxia . These results suggest that both KAP 1 and the concurrence of RBS +HRE within the RTA promoter are essential for KSHV latency and hypoxia-induced lytic reactivation .Kaposi 's sarcoma -associated herpesvirus (KSHV ), a DNA tumor virus , is an etiological agent linked to several human malignancies , including Kaposi 's sarcoma (KS ) and primary effusion lymphoma (PEL ). HIF-1 Î±, a key hypoxia-inducible factor , is frequently elevated in KSHV latently infected tumor cells and contributes to KSHV lytic replication in hypoxia . The molecular mechanisms of how KSHV controls the latent and lytic life cycle through deregulating HIF-1 Î± remain unclear . In this study , we found that inhibition of hypoxia-sensitive chromatin remodeler KAP 1 in KSHV-infected PEL cells leads to a loss of viral genome and increases its sensitivity to hypoxic stress , leading to KSHV lytic reactivation . Importantly , we also found that four hypoxia-responsive clusters within the KSHV genome contain a high concurrence of RBP-J Îº (a key cellular regulator involved in Notch signaling ) and HIF-1 Î± binding sites . These sites are also tightly associated with KAP 1 . This discovery implies that KAP 1 , RBP-J Îº , and HIF-1 Î± play an essential role in KSHV pathogenesis through subtle cross talk which is dependent on the oxygen levels in the infected cells .

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primary effusion lymphoma

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