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Pathogenetic Influences of Human Herpesvirus 8 (HHV-8) in Prostate Cancer Progression
Uniformed Services University Of The Health Sciences Bethesda United States
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The mechanisms that give rise to androgen-independent prostate cancer AIPCare incompletely understood, resulting in a lack of treatment options for this fatal form of the disease. It is believed that most cases of AIPC are the result of constitutive activation of the androgen receptor AR pathway, leading us to hypothesize that chronic, prostatic infection could promote cancer progression as a result of pathogen virulence factors activating cell signaling pathways known to induce AR signaling. We found that humanherpesvirus-8 HHV-8 infection of androgen-sensitive LNCaP cells promotes AI cell proliferation. Contrary to our initial hypothesis, we found that, despite enhanced AI cell proliferation, HHV-8-infected LNCaP LNCaPv219 cells have decreased expression of both AR and AR-regulated genes such as prostate-specific antigen PSA, implying that the phenotype induced by HHV-8 occurs concomitantly with decreased AR signaling. It is known that HHV-8 maintains latency by epigenetically suppressing lytic gene expression though histone methyltransferase activity by the Polycomb group protein EZH2, which coincidentally has been shown to be up-regulated in advanced, metastatic prostate cancer tissues. We found that increased EZH2 expression in LNCaPv219 cells results in epigenetic silencing of two tumor-suppressing proteins, microseminoprotein-MSMB and DAB2-interacting protein DAB2IP. Additionally, we found thatLNCaPv219 cells have adopted a pro-mesenchymal phenotype, evidenced by increased expression of mesenchymal markers N-cadherin and vimentin and decreased expression of the epithelial marker E-cadherin. Collectively, these results suggest that HHV-8infection promotes an AI phenotype that mimics the EZH2-mediated transcriptional profile of poorly differentiated prostate tumors.
APPROVED FOR PUBLIC RELEASE