New Insights into Epstein-Barr Virus Protein's Role in Cancer Development

Researchers at The Wistar Institute have made significant strides in understanding how a specific protein from the Epstein-Barr virus (EBV), known as EBNA-LP, alters DNA structure in B cells, potentially leading to cancer.

The findings, published in the journal Nucleic Acids Research, illustrate that EBNA-LP can open up previously restricted areas of the immune cell's genome, creating new pathways that may encourage the growth of cancerous cells. Italo Tempera, an associate professor at Wistar's Ellen and Ronald Caplan Cancer Center, emphasized the groundbreaking nature of this discovery, highlighting that it marks the first instance where the capability of EBNA-LP to commandeer host cell functions has been clearly demonstrated.

EBV is a common virus, infecting over 90% of the global population, and often results in mild or no symptoms. However, for some individuals, it can lead to severe health issues, including various cancers and autoimmune disorders like multiple sclerosis. Understanding the molecular mechanisms by which EBV induces such transformations is crucial for developing targeted therapies.

Previously viewed as a mere supporting protein, EBNA-LP's role is now understood to be more complex. The research team employed a technique called HiChIP, which combines Hi-C with chromatin immunoprecipitation, to demonstrate EBNA-LP's unique interaction with YY1, a protein that plays a key role in organizing the three-dimensional structure of DNA within B cells. This interaction alters the way the genome is folded, allowing sections of DNA that are typically inaccessible to be expressed.

Tempera explained the analogy of the genome as a library, where some sections are easily accessible while others remain locked. EBNA-LP acts like a key, unlocking these restricted areas and facilitating access to genomic regions that should ordinarily remain dormant.

This alteration causes mature B cells to revert to a more stem-like state, characterized by increased plasticity, which can enhance their responsiveness to signals that promote cancer growth. EBNA-LP's influence is part of a broader strategy employed by EBV, which also utilizes two other proteins, EBNA1 and EBNA2, to manipulate B cell genome structure. The evolution of multiple viral proteins targeting the same cellular processes underscores the importance of this mechanism for the virus's success in infection.

Tempera pointed out the existing challenges in treating EBV-related diseases, as current methods focus on managing symptoms rather than targeting the virus itself. This research offers critical insights that could pave the way for therapies specifically aimed at EBV.

Moreover, the study suggests that similar mechanisms of genome restructuring may also be present in other cancers caused by genetic mutations, opening the door to potentially new and broader therapeutic strategies. Tempera noted that viruses typically do not create new cellular mechanisms but instead repurpose existing biological tools for their benefit. By investigating how EBV manipulates these mechanisms, researchers can gain valuable insights into fundamental biological processes that may also be disrupted in various cancers.

These findings not only enhance our understanding of EBV's role in cancer but also highlight potential avenues for future research and treatment strategies that could address the gap in current therapeutic options.