Chromatin remodeling controls Kaposi's sarcoma-associated herpesvirus reactivation from latency

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of three human malignancies, the endothelial cell cancer Kaposi’s sarcoma, and two B cell cancers, Primary Effusion Lymphoma and multicentric Castleman’s disease. KSHV has latent and lytic phases of the viral life cycle, and while both contribute to viral pathogenesis, lytic proteins contribute to KSHV-mediated oncogenesis. Reactivation from latency is driven by the KSHV lytic gene transactivator RTA, and RTA transcription is controlled by epigenetic modifications. To identify host chromatin-modifying proteins that are involved in the latent to lytic transition, we screened a panel of inhibitors that target epigenetic regulatory proteins for their ability to stimulate KSHV reactivation. We found several novel regulators of viral reactivation: an inhibitor of Bmi1, PTC-209, two additional histone deacetylase inhibitors, Romidepsin and Panobinostat, and the bromodomain inhibitor (+)-JQ1. All of these compounds stimulate lytic gene expression, viral genome replication, and release of infectious virions. Treatment with Romidepsin, Panobinostat, and PTC-209 induces histone modifications at the RTA promoter, and results in nucleosome depletion at this locus. Finally, silencing Bmi1 induces KSHV reactivation, indicating that Bmi1, a member of the Polycomb repressive complex 1, is critical for maintaining KSHV latency.

Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?

“…KSHV reactivation, and subsequent oncolysis, was only initiated when cells were co-treated with JQ1 and an NF-κB-activating compound (PEP005) (Zhou et al, 2017 ). This is in contrast to reports elsewhere of KSHV reactivation with BET BRDi alone (Chen et al, 2017 ; Hopcraft et al, 2018 ), although the disparity in results may be due to the range of PEL cell and reporter lines used across all of these studies, some of which are also EBV-positive. In a sophisticated study, the Lieberman laboratory resolved the molecular mechanism of BET BRDi-induced KSHV reactivation; using JQ1, they showed that the three-dimensional (3D) looping conformation of the KSHV genome that maintains the expression of latent transcripts (Chen et al, 2013 ) was destabilized such that lytic expression ensued (Chen et al, 2017 ).…”

Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV

“…H3K27me3, H3K9me3, and hypoacetylated histones) [6,7]. The repression of lytic genes during latency can be achieved by various inhibitory epigenetic and transcriptional mechanisms such as DNA methylation [8], Polycomb Repressive Complex 1 (PRC1)-and PRC2-mediated histone modifications [6,7,9], histone deacetylation [10,11,12,13], viral chromosome looping [14,15], and NELF-mediated transcription elongation inhibition [16]. Of the lytic genes, the transcriptional regulation of ORF50, which encodes the viral replication and transcription activator (RTA), has been studied in more detail because of its essential role in the lytic cycle [17].…”

Inhibition of polo-like kinase 1 (PLK1) facilitates reactivation of gamma-herpesviruses in B-cell lymphomas and their elimination

“…Recently, it has been reported that PLK1 inhibition significantly reduces the downstream c-Myc phosphorylation and impairs BRD4 binding to the c-Myc gene inhibiting c-Myc transcription 56 . Our study demonstrated that PLK1 inhibition induced KSHV reactivation involves c-Myc (Fig 5), which further affects the level of H3K27me3 suppressive mark that associates with the repressed transcription of KSHV lytic genes 57 . In this study we successfully delineated that the connection of PLK1 inhibition with c-Myc dysregulation and the subsequent change of histone methylation marks.…”