Characterization of molecular mechanisms driving Merkel cell polyomavirus oncogene transcription and tumorigenic potential

ABSTRACT: Merkel cell polyomavirus (MCPyV) is associated with approximately 80% of cases of Merkel cell carcinoma (MCC), an aggressive type of skin cancer. The incidence of MCC has tripled over the past twenty years, but there are currently very few effective targeted treatments. A better understanding of the MCPyV life cycle and its oncogenic mechanisms is needed to unveil novel strategies for the prevention and treatment of MCC. MCPyV infection and oncogenesis are reliant on the expression of the early viral oncoproteins, which drive the viral life cycle and MCPyV+ MCC tumor cell growth. To date, the molecular mechanisms regulating the transcription of the MCPyV oncogenes remain largely uncharacterized. In this study, we investigated how MCPyV early transcription is regulated to support viral infection and MCC tumorigenesis. Our studies established the roles of multiple cellular factors in the control of MCPyV gene expression. Inhibitor screening experiments revealed that the histone acetyltransferases p300 and CBP positively regulate MCPyV transcription. Their regulation of viral gene expression occurs through coactivation of the transcription factor NF-κB, which binds to the viral genome to drive MCPyV oncogene expression in a manner that is tightly controlled through a negative feedback loop. Furthermore, we discovered that small molecule inhibitors specifically targeting p300/CBP histone acetyltransferase activity are effective at blocking MCPyV tumor antigen expression and MCPyV+ MCC cell proliferation. Together, our work establishes key cellular factors regulating MCPyV transcription, providing the basis for understanding the largely unknown mechanisms governing MCPyV transcription that defines its infectious host cell tropism, viral life cycle, and oncogenic potential. Our studies also identify a novel therapeutic strategy against MCPyV+ MCC through specific blockage of MCPyV oncogene expression and MCC tumor growth. Author summary MCPyV is a ubiquitous skin infection that can cause one of the most aggressive and highly fatal skin cancers, MCC, which has been increasing in incidence in the decades since its initial discovery. Despite the growing concern presented by this cancer, there are currently no effective targeted therapies to treat MCC. MCC metastasizes rapidly and resists currently available chemotherapy and immune checkpoint inhibitor treatment strategies in a significant portion of patients. Approximately 80% of MCCs are caused by MCPyV, which normally maintains asymptomatic infection within the skin but in rare cases drives MCPyV+ MCC oncogenesis through the expression of the viral oncogenes. Our characterization of the largely unknown molecular mechanisms controlling MCPyV gene expression furthers our understanding of the link between MCPyV infection and MCC oncogenesis. Our study also identifies druggable targets that are exploitable to specifically repress MCPyV oncogene expression and MCC tumor growth. This work demonstrates that hampering viral oncogene transcription is a novel and effective therapeutic strategy to obliterate MCPyV-induced MCC tumorigenesis.

SUBMITTER: Yang J 

PROVIDER: S-EPMC10468096 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature