The lab of Erle Robertson, PhD, professor of Microbiology, and program leader of Tumor Virology at Penn’s Abramson Cancer Center, has been studying how Kaposi’s Sarcoma-associated Herpes Virus (KSHV) subverts normal cell machinery to cause cancer for more than a decade.
Kaposi’s sarcoma is a type of cancer caused by an associated herpesvirus. In the US, it usually occurs in people with a weak immune system caused by AIDS or in other immune-compromised individuals, and before the AIDS epidemic, Kaposi sarcoma was considered rare. At that time, about two new cases were found for every million people each year, according to the National Cancer Institute. With the AIDS epidemic, the incidence of the sarcoma in the US increased by 20 times, peaking at about 47 cases per million people (per year) in the early 1990s. Now, with new treatments for AIDS, the sarcoma occurrence is about six cases per million people each year, according to the American Cancer Society.
A KSHV protein called the latency-associated nuclear antigen, LANA for short, helps the KS herpesvirus hide out from the immune system in infected cells over long periods of time – the latency. Normally LANA performs multiple functions, including regulating parts of the immune response against a range of pathogenic agents. When LANA takes the place of other proteins that control cell growth, it can cause uncontrolled cell replication.
Previous studies by Robertson and colleagues showed that LANA stabilizes a crucial protein called Notch, a signaling molecule that triggers cell development and maintains the stability of cells in such organs as the brain, heart, blood, and muscle.
Recently, the Robertson lab found that LANA can drastically reduce the expression of cell surface proteins that coordinate communication between white blood cells and other cells, described in a study published in PLOS Pathogens, thereby affecting the body’s response to viral infections. In another study, also published in PLOS Pathogens, the lab showed that LANA can also regulate viral latency through a molecular switch. This switch is a modification of the LANA protein by the addition or subtraction of a small peptide called SUMO, which acts as a toggle to reactivate the sleeping virus based on oxygen levels in cells.
Tumors at the extremities of the body are typically low in oxygen, a condition called hypoxia. In normal oxygen conditions, the addition of SUMO to LANA represses viral genes by recruiting other proteins called co-repressor complexes. This blocks virus replication and so maintains latency of the virus. In low-oxygen conditions SUMO is removed and the co-repressor complex is released, activating virus proteins important for their own replication.
These two studies show how the flexibility of the LANA protein and its associated molecular partners have a direct role in regulating immune responses as well as reactivating viral genes during low-oxygen conditions. “These studies have a potential impact in designing new therapeutic approaches for treating KSHV-associated cancers,” says Robertson.