Kaposi's sarcoma-associated herpesvirus (KSHV) causes life-long
latent infection and
malignancies, including KS commonly found in
AIDS patients. Lytic replication can be induced to kill
tumor cells harboring latent KSHV, through viral cytopathic effects and the subsequent
antiviral immune responses. Viral
FLICE-inhibitory protein (vFLIP), encoded by KSHV ORF K13, inhibits KSHV lytic reactivation, implying that the
competing endogenous RNA (
ceRNA) networks regulated by vFLIP can be modulated to induce the lytic reactivation of latent KSHV, a promising strategy for KSHV-associated
malignancies. Here, we performed whole-transcriptome sequencing to reveal the global landscape of noncoding RNAs and messenger RNAs (mRNAs) in iSLK-RGB-BAC16 cells and iSLK-RGB-K13 mutant cells. It showed that vFLIP regulated 227 differentially expressed (DE) long non-coding RNAs (lncRNAs), 57 DE circular RNAs (
circRNAs), 20 DE
microRNAs (
miRNAs), and 1371 DE mRNAs. Enrichment analysis verified that
riboflavin metabolism was simultaneously enriched in DE genes related to
miRNAs, lncRNAs, and
circRNAs. The upregulated hsa-miR-378i and
hsa-miR-3654, and downregulated miR-4467, miR-3163, miR-4451, and miR-4257 were significantly enriched in the
ceRNA complex network, which contained 9 upregulated and 7 downregulated
circRNAs, 5 upregulated and 85 downregulated lncRNAs, 5 upregulated and 35 downregulated mRNAs. Finally, we constructed and validated two vFLIP-regulated
ceRNA networks:
circRNA hsa_circ_0070049/hsa-miR-378i/SPEG/FOXQ1 and
lncRNA AL031123.1/hsa-miR-378i/SPEG/FOXQ1. Taken together, the two
ceRNA networks may mediate KSHV reactivation. These novel findings refreshed the present understanding of
ceRNA network in KSHV lytic induction and provided potential therapeutic targets for KSHV-associated
malignancies.