Scientists have discovered key factors that control the genome maintenance and replication of a virus responsible for a rare form of cancer.

An international team of scientists led by Professor Päivi Ojala at the University of Helsinki have published new findings in Cancer Research, which reveal key factors that control the genome maintenance and replication of a virus responsible for Kaposi’s sarcoma (KS), a rare type of cancer.

KS is caused by a form of herpesvirus and is the most common cancer among AIDS patients. It is also often seen in sub-Saharan and Mediterranean populations or after graft transplant. Current research suggests that KS originates from the endothelium - the thin membrane that lines the inside of the heart and blood vessels - in immunocompromised individuals.

The virus displays two phases of infection, latency and lytic, with both contributing to the formation of tumours. Latency represents the default mode of infection in virtually all susceptible cell types. Lymphatic endothelial cells (LEC), the suggested KS tumour cells precursors, display a unique viral infection program with spontaneous lytic gene expression as well as high intra- and extracellular viral load.

Unexpected findings

In the new paper, Professor Ojala's team address a long-standing question: What is the molecular cause of the spontaneous lytic phase observed in KSHV-infected primary human lymphatic endothelial cells (KLECs)?

“The research group discovered that two central proteins that directly regulate gene expression on the DNA are key factors, control the genome maintenance and replication of a virus responsible for lymphatic vascular cancer. These two factors support the virus-induced tumour formation and represent new attractive therapeutic targets,” explains Professor Ojala.

Dr Silvia Gramolelli, an Academy of Finland post-doctoral researcher at the University of Helsinki, investigated the role in Kaposi Sarcoma of PROX1, SOX18 and COUPTF2, the three key transcription factors (TFs) governing the birth of the lymphatic vasculature during embryonic development.

The results of the study demonstrate that all three key factors are expressed in a cohort of KS tumours concomitant with unexpectedly prominent marker of the late lytic phase, the protein K8.1.

“Key transcription factors SOX18 and PROX1 expressions are crucial to support the spontaneous and productive KSHV lytic infection program in LECs, and their expression in tumours correlates with lytic and latent markers of infection,” says Dr Gramolelli.

This finding overturns the notion that KS tumour cells are predominantly latently infected and indicates that lytic gene expression is far more abundant than previously thought.

“To our surprise, SOX18 and PROX1 regulate two different and complementary processes in the virus oncogenic replication cycle independently from each other,” says Dr Gramolelli.

“While PROX1 enhances the viral lytic gene expression, SOX18 is involved in the maintenance of a higher number of viral genome copies. Besides revealing an exciting insight on the KSHV infection program in endothelial cells, this study uncovers how the virus mechanistically hijacks PROX1 and SOX18 to its genome to support its own replication and lytic gene expression,” Dr Gramolelli adds.

A new therapeutic avenue for KS?

Despite decades of research, no standard treatment for KS has been established. Clinical outcomes are particularly unfavourable, especially in resource-limited communities.

The research group discovered, in collaboration with Associate Professor Mathias Francois (The Centenary Institute, University of Sydney), that both a SOX18 small molecule inhibitor previously developed by Francois and the R-enantiomer of an FDA-approved beta-blocker, propranolol, showed a striking reduction in intracellular and extracellular viral loads in vitro.

“These findings suggest a potential, novel therapeutic avenue for KS, but further work is required to see if it will be possible to apply them to design new KS therapeutic strategies targeting SOX18,” Professor Ojala comments.

This article is adapted from a press release by the University of Helsinki. 

'Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production' by Silvia Gramolelli et al. is published in Cancer Research