Targeting PARP1 Activity May Be An Effective Treatment For Some Epstein-Barr Patients

The Epstein-Barr virus (EBV) is a member of the herpes virus family and is one of the most common human viruses. Up to 95% of people will get infected with EBV at some point in their lives, with the virus spreading most commonly through bodily fluids, primarily saliva. After a person is infected with EBV, the virus becomes latent (inactive) and persists for the rest of that individual’s life in the B cells of their immune system. In some cases, the virus may reactivate. This does not always cause symptoms, but people with weakened immune systems are at a much higher risk. EBV is best known as the cause of infectious mononucleosis, also called mono or glandular fever.

EBV is also associated with various cancers of the immune system, where it persists in its latent form, including Burkitt and Hodgkin’s lymphomas. Additionally, EBV is causative of lymphoproliferative disease in people with suppressed immune systems, such as post-transplant and HIV/AIDS patients. However, in most cases, the approach to these EBV-positive cancers does not differ from EBV-negative cancers of the same nature. This is despite EBV-positive cancers often having a worse prognosis over their EBV-negative counterparts. Therefore, it is important to target EBV in these cancers to find more effective, targeted treatments for EBV-positive cancers.

One of the key viral genes enabling EBV to contribute to cancer cell formation is LMP1. LMP1 can activate enzymes in human cells that impact their normal gene expression patterns. Once such enzyme that LMP1 can activate is PARP1. PARP1 activity can influence the way in which the DNA is packed inside the nucleus of the cells. By relaxing or condensing DNA, PARP1 can regulate the accessibility to the genetic information stored in the DNA. Activation of PARP1, therefore, regulates the expression of genes by influencing the way in which the genetic information is packed into the nucleus and can often lead to an increase in the number of genes that are ‘turned on’ in a cell.

Our group discovered that by activating PARP1 EBV can regulate the expression of several genes that are often overexpressed in EBV-positive malignancies. Among these genes, our group found HIF-1α. HIF-1α is usually present at a high level in many different types of cancers. HIF1A plays an important role in regulating the way in which cells respond to changes in the oxygen levels in our body. Under normal conditions, HIF1A coordinates the adaptive response of the cell to low oxygen level by promoting vascularization and changes in the way cells use their energy. However, in cancer, the unrestricted action of HIF1A contributes to the survival of the cancer cells and consequently tumor invasion.

In our work, we found that LMP1/PARP1 led to HIF-1α–dependent changes in cellular metabolism. Consequently, when we introduced LMP1 to human cells they underwent a ‘switch’ in their metabolism. Normally, when cells have access to abundant oxygen, they will use a process called mitochondrial respiration to generate energy for the cell as it is by far the most efficient way to so. However, we found that when we added LMP1 to cells, their metabolism was altered to primarily rely on a process called aerobic glycolysis for their energy requirements. Glycolysis is far less efficient at generating energy versus mitochondrial respiration and is, therefore, normally performed as ‘anaerobic’ glycolysis, such as during strenuous exercise which leads to prolonged oxygen depletion in muscle cells. However, many cancer cells display a phenomenon known as the ‘Warburg effect,’ also known as aerobic glycolysis, which is the high rate of glycolysis even in the presence of abundant oxygen. Warburg metabolism is thought to enable rapid cell division (a hallmark of cancer cells) through increased glucose consumption, yielding metabolic byproducts that the cell can use as ‘building blocks’ for cellular components, allowing the cell to grow and divide more quickly than normal cells.

We found that when we treated cells with the FDA-approved drug olaparib, a PARP1 inhibitor, we could eliminate the LMP1-induced increase in HIF-1α-dependent gene expression, the alteration of cellular metabolism, and the subsequent accelerated cellular proliferation. Therefore, targeting PARP1 activity may be an effective treatment for LMP1+ EBV-associated malignancies, which currently lack therapeutic interventions.

These findings are described in the article entitled Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1, recently published in the journal PLOS Pathogens.

About The Author

Italo Tempera

Dr. Tempera’s research focuses on understanding the functional links between epigenetic domains, chromosome conformation and gene expression in the context of cancer. Chromatin composition and organization represent an important element in regulating genome function. The analysis of chromosome conformation in yeast and Drosophila promoted the view of the genome as a set of physical domains that correlate with the epigenetic domains, suggesting a strong link between genome structure and genome function.

Our goal is to understand how the chromatin three-dimensional structure affects gene expression and how cancer can alter this process.

In particular we study the role of epigenetic modifications into the mechanism regulating Epstein-Barr virus (EBV) latency since EBV latent infection has been causally linked to a variety of B-cell and epithelial malignancies. EBV is able to establish a life-long latent infection persisting in memory B-lymphocytes as a chromatin-associated multicopy mini-chromosome adopting different gene expression programs that are referred to as latency types. These different latency types are epigenetically stable and correspond to different promoter utilization and depend on the host cell type and the nature of the tumor from which EBV is isolated. Hence, EBV represents a useful system for gaining a new insight into the basic understanding of the role of chromatin architecture in gene expression regulation in mammals. EBV studies are also instrumental in clarifying how cancer manipulates the epigenome for continued neoplastic growth and adaptability.

Michael Hulse

Michael Hulse is a PhD Student at Temple University. Michael graduated from the University of Edinburgh in 2012 with an MSc in Biomedical Sciences. Following this, he spent two years working for AstraZeneca in their oncology department analyzing pharmacodynamic endpoints as part of drug discovery research projects. He subsequently spent a year at MedImmune working in Analytical Development to introduce and validate assays for Influenza vaccine quality control. He is now in Dr. Tempera’s lab where he has been focused on understanding the mechanisms by which Epstein-Barr Virus Latent Membrane Protein 1 modifies host gene expression.

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