Abstract
Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)-mediated epigenetic silencing of tumor-suppressor genes, including MSMB and DAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer.
Highlights
Prostate cancer is the most commonly diagnosed, noncutaneous malignancy responsible for more than 10% of all cancer-related deaths in the United States [1]
Infection was confirmed by immunofluorescence assay designed to detect the viral latency-associated nuclear antigen (LANA), which maintains viral latency in part by tethering the viral episome to the host chromosome [21]; the characteristic punctate foci of nuclear LANA staining in chronically infected cells can be seen in LNCaP-v219 cells (Fig. 1C) and in DU145-v219 cells (Supplementary Fig. S1A) that support robust virus reactivation upon treatment with a subtoxic dose of n-butyrate (Supplementary Fig. S1B)
Contrary to a previous report [22], human herpesvirus 8 (HHV-8) is capable of establishing a latent infection in both androgendependent and -independent cell lines, which is important as a basis for testing whether this oncogenic virus can skew androgen-dependent prostate cancer cell growth toward an androgen-independent state
Summary
Prostate cancer is the most commonly diagnosed, noncutaneous malignancy responsible for more than 10% of all cancer-related deaths in the United States [1]. Growth and survival of prostate cancer cells relies heavily on androgens, which, upon binding to the androgen receptor (AR), activate transcription of androgen-responsive genes that drive cancer progression [2]. The firstline standard-of-care treatment of localized early-stage disease is androgen-deprivation therapy ADT is initially efficacious, many cases progress to the aggressive, metastatic state that is refractory to hormone deprivation, at which point the cancer becomes castration-resistant or androgen-independent. Authors' Affiliation: Emerging Infectious Diseases Program, Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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