Abstract 3500: Epstein-Barr virus BART noncoding RNAs modulate host gene expression for virus latency leading to oncogenesis in epithelial cells
Authors: Rob Verhoeven, Bobo Wing-Yee Mok, Shuang Tong, Honglin Chen
Journal: Cancer Research (2017)

Abstract Epstein-Barr virus (EBV) efficiently establishes and maintains a state of latency in resting B cells, with persistent asymptomatic infections occurring in more than 95% of the human population worldwide. Besides causing lifelong infections in resting B cells in the majority of people, EBV has been found to associate with several human cancers occurring in immune competent individuals, in which the virus expresses very few viral proteins in EBV infected cancer cells through a distinct viral latency program. It is believed that this type of mechanism has been adopted by EBV to allow the virus to evade host immune surveillance. Nasopharyngeal carcinoma (NPC) is prevalent in southern China, Southeast Asian countries and some African countries but uncommon in rest of the world. In NPC 100% of cancer cells are infected with EBV, and EBV is recognized one of the major etiological factors. However, the details of how EBV maintains latency and contributes to the oncogenesis of NPC remain mostly elusive. Notably, EBV abundantly expresses a family of non-coding RNAs derived from the BamHI A region of the viral genome (BARTs). It is hypothesized that this family of viral non-coding RNAs is key to maintaining viral latency, evading immune surveillance and triggering oncogenesis in EBV associated tumors. We have shown a mechanism for the regulation of the abundant expression of BARTs in NPC which involves the constitutive activation of NF-κB signaling typically observed in NPC cells and have also identified a regulatory loop through which BARTs support EBV latency in NPC. Using high throughput RNA-seq analysis we further demonstrated that BART RNAs modulate expression of cellular genes associated with anti-inflammatory and immune-modulating properties, oxidoreductase activity, and cell migration and invasion in NPC cells. BART non-coding RNAs are predominantly localized in the nucleus and associate with the CBP/p300 complex. Our data showed that EBV BARTs modulate genes responsive to the mitochondria-associated adapter molecule (MAVS) through halting cellular Pol II in the promoter region and downregulating gene expression. In the nucleus, BART non-coding RNAs modulate chromatin acetylation through interaction with CBP/p300. We have generated a working model with evidence showing that Epstein-Barr virus shuts off most of the viral proteins to evade immune surveillance, but through expression of high levels of BART non-coding RNAs can modulate cellular gene expression to provide an optimal environment for maintenance of viral latency in cancer cells. Alteration of cellular gene expression by EBV BART non-coding RNAs for establishment and maintenance of EBV latency in epithelial cells can therefore lead to the oncogenic process for EBV associated tumors. Citation Format: Rob Verhoeven, Bobo Wing-Yee Mok, Shuang Tong, Honglin Chen. Epstein-Barr virus BART noncoding RNAs modulate host gene expression for virus latency leading to oncogenesis in epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3500. doi:10.1158/1538-7445.AM2017-3500