LINE-1 transposable element is expressed in Kaposi’s sarcoma and regulates gene expression in KSHV-infected cells

Long interspersed nuclear element-1 (LINE-1/L1) retrotransposons are expressed in various human cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which are characterized by global transcriptional reprogramming. Previously, we have found upregulation of L1 in PEL. Here, we show that knockdown of L1 in PEL cells significantly impaired their proliferation and induced broad transcriptional changes encompassing DNA replication, mitotic progression, and genome maintenance pathways. Analysis of KSHV-infected mouse and human mesenchymal stem cell models revealed that the KS-mimicking microenvironment robustly upregulates L1 expression, with sustained expression observed in KSHV-induced tumor cells even after the loss of the viral episome. Reanalysis of RNA-seq data from KS patient biopsies further showed elevated L1 expression in both endemic and AIDS-associated epidemic KS, with partial reduction following antiretroviral therapy. L1 ORF1p protein expression was confirmed by immunohistochemistry in KS tissues. Reanalysis of the enzymes that can modulate DNA methylation, a process that regulates L1 expression, revealed upregulation of DNMT3A and TET2 in both mouse KSHV tumor models and human KS. Altogether, our findings establish the L1 activation as a hallmark of KSHV-driven oncogenesis.