Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production

Oncogenic Herpesvirus Engages Endothelial Transcription Factors SOX18 and PROX1 to Increase Viral Genome Copies and Virus Production.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1158/0008-5472.CAN-19-3103
Journal or Publication Title: Cancer Research
Volume: 80
Number: 15
Page Range: pp. 3116-3129
Date: 2020
Divisions: David Richmond program for Cardiovascular Development
Depositing User: General Admin
Identification Number: 10.1158/0008-5472.CAN-19-3103
ISSN: 0008-5472
Date Deposited: 04 Jan 2021 01:26

Kaposi sarcoma is a tumor caused by Kaposi sarcoma herpesvirus (KSHV) infection and is thought to originate from lymphatic endothelial cells (LEC). While KSHV establishes latency in virtually all susceptible cell types, LECs support spontaneous expression of oncogenic lytic genes, high viral genome copies, and release of infectious virus. It remains unknown the contribution of spontaneous virus production to the expansion of KSHV-infected tumor cells and the cellular factors that render the lymphatic environment unique to KSHV life cycle. We show here that expansion of the infected cell population, observed in LECs, but not in blood endothelial cells, is dependent on the spontaneous virus production from infected LECs. The drivers of lymphatic endothelium development, SOX18 and PROX1, regulated different steps of the KSHV life cycle. SOX18 enhanced the number of intracellular viral genome copies and bound to the viral origins of replication. Genetic depletion or chemical inhibition of SOX18 caused a decrease of KSHV genome copy numbers. PROX1 interacted with ORF50, the viral initiator of lytic replication, and bound to the KSHV genome in the promoter region of ORF50, increasing its transactivation activity and KSHV spontaneous lytic gene expression and infectious virus release. In Kaposi sarcoma tumors, SOX18 and PROX1 expression correlated with latent and lytic KSHV protein expression. These results demonstrate the importance of two key transcriptional drivers of LEC fate in the regulation of the tumorigenic KSHV life cycle. Moreover, they introduce molecular targeting of SOX18 as a potential novel therapeutic avenue in Kaposi sarcoma.

Gramolelli, Silvia
Elbasani, Endrit
Tuohinto, Krista
Nurminen, Veijo
Günther, Thomas
Kallinen, Riikka E.
Kaijalainen, Seppo P.
Diaz, Raquel
Grundhoff, Adam
Haglund, Caj
Ziegelbauer, Joseph M.
Pellinen, Teijo
Bower, Mark
Francois, Mathias
Ojala, Päivi M.
Last Modified: 04 Jan 2021 01:26
URI: https://eprints.centenary.org.au/id/eprint/785

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