Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) preferentially infects and causes Kaposi's sarcoma (KS) in male patients. However, the biological mechanisms are largely unknown. This study was novel in confirming the extensive nuclear distribution of the androgen receptor (AR) and its co-localization with viral oncoprotein of latency-associated nuclear antigen in KS lesions, indicating a transcription way of AR in KS pathogenesis. The endogenous AR was also remarkably higher in KSHV-positive B cells than in KSHV-negative cells and responded to the ligand treatment of 5α-dihydrotestosterone (DHT), the agonist of AR. Then, the anti-AR antibody-based chromatin immunoprecipitation (ChIP)-associated sequencing was used to identify the target viral genes of AR, revealing that the AR bound to multiple regions of lytic genes in the KSHV genome. The highest peak was enriched in the core promoter sequence of polyadenylated nuclear RNA (PAN), and the physical interaction was verified by ChIP-polymerase chain reaction (PCR) and the electrophoretic mobility shift assay (EMSA). Consistently, male steroid treatment significantly transactivated the promoter activity of PAN in luciferase reporter assay, consequently leading to extensive lytic gene expression and KSHV production as determined by real-time quantitative PCR, and the deletion of nuclear localization signals of AR resulted in the loss of nuclear transport and transcriptional activity in the presence of androgen and thus impaired the expression of PAN RNA. Oncogenically, this study identified that the AR was a functional prerequisite for cell invasion, especially under the context of KSHV reactivation, through hijacking the PAN as a critical effector. Taken together, a novel mechanism from male sex steroids to viral noncoding RNA was identified, which might provide a clue to understanding the male propensity in KS.
Highlights
Kaposi’s sarcoma (KS) occurs predominantly in men in the classic type or endemic population, and the male-to-female ratio ranges from 10:1 to 15:1 [1,2,3]
High-throughput chromatin immunoprecipitation sequencing analysis showed that the androgen receptor (AR) had extensive binding sites in the KS-associated herpesvirus (KSHV) genome, in which the highest enriched gene was polyadenylated nuclear RNA (PAN)
PAN exhibited the strongest upregulation of promoter activity and RNA transcription among various KSHV lytic genes after the male hormone treatment
Summary
Kaposi’s sarcoma (KS) occurs predominantly in men in the classic type or endemic population, and the male-to-female ratio ranges from 10:1 to 15:1 [1,2,3]. The male propensity is partly explained by sex-related differences in environmental influences and behaviors, for example, iron uptake and alcohol consumption, implying that host genetic factors are crucial determinants [4,5]. Researchers have made great efforts to elucidate the roles of host hormones in virus infection and/or pathogenesis, considering severe progression in male patients during the COVID-19 pandemic [6,7,8]. The KS incidence and the infection by its causative agent, KS-associated herpesvirus (KSHV), exhibited male propensity in a diverse cohort study. In Africa, the age-standardized incidence rate of KS was three times more in men than in women [13,14,15], and the KSHV virus load has been found to be higher in men [16,17].
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