MCV Truncated Large T antigen interacts with BRD4 in tumors

Abstract

Among Polyomaviridae family of viruses, Merkel Cell Polyomavirus (MCV) is the only human polyomavirus with convincing data supporting its classification as a direct causative agent of a human skin malignancy, Merkel Cell Carcinoma. Oncogenic transformation by MCV requires the integration of the viral genome into the human genome, truncation of the large T antigen (LT) to render the viral genome replication deficient and expression of small T antigen oncoprotein. The chromatin binding protein BRD4, was recently shown to transcriptionally regulate the expression of virus oncoproteins, thereby enhancing the tumorigenesis of virus-associated cancers, such as HPV associated cervical cancer. Previous work by Wang et al. revealed that BRD4 interacts with MCV full length LT during viral replication. In this study, we demonstrated that MCV truncated tumor LT antigen also interacts with BRD4 protein. We showed that the MCV tumor LT antigen and BRD4 protein complex co-localizes within the nucleus. Furthermore, we tested whether BRD4 protein transcriptionally regulates MCV Non Coding Control Region (NCCR), where we found that though full length LT and sT together, along with the BRD4 protein showed enhanced transcriptional activity whereas tumor truncated LT did not. These findings on the interactions of the MCV tumor truncated LT antigen with the BRD4 protein add to existing knowledge about interactions with LT and its role in tumorigenesis, and assist in efforts to more precisely define new therapy targets for this disease.