A nuclear NKRF interacting long noncoding RNA controls EBV eradication and suppresses tumor progression in natural killer/T-cell lymphoma

Long intergenic noncoding RNAs (lincRNAs) are differentially expressed in EBV-infected cells and play an essential role in tumor progression. Molecular pathogenesis of lincRNAs in EBV-driven natural killer T cell lymphoma (NKTCL) remains unclear. Here we investigated the ncRNA profile using high-throughput RNA sequencing data of 439 lymphoma samples and screened out LINC00486, whose downregulation was further validated by quantitative real-time polymerase chain reaction in EBV-encoded RNA (EBER)-positive lymphoma, particularly NKTCL. Both in vitro and in vivo studies revealed the tumor suppressive function of LINC00486 through inhibiting tumor cell growth and inducing G0/G1 cell cycle arrest. As mechanism of action, LINC00486 specifically interacted with NKRF to abrogate its binding with phosphorylated p65, activated NF-KB/TNF-a signaling and subsequently enhanced EBV eradication. Solute carrier family 1 member 1 (SLC1A1), upregulated and mediated the glutamine-addiction and tumor progression in NKTCL, was negatively correlated with the expression of NKRF. NKRF specifically bound to the promoter and transcriptionally downregulated the expression of SLC1A1, as evidenced by Chromatin Immunoprecipitation (ChIP) and luciferase assay. Collectively, LINC00486 functioned as a tumor suppressor and counteracted EBV infection in NKTCL. Our study improved the knowledge of EBV-driven oncogenesis in NKTCL and provided the clinical rationale of EBV eradication in anticancer treatment.

Automated summary

This study identified a long intergenic noncoding RNA, LINC00486, which is downregulated in lymphoma cells infected with Epstein-Barr virus (EBV), especially in natural killer T cell lymphoma (NKTCL). LINC00486 was found to have tumor-suppressive effects by inhibiting tumor cell growth and inducing cell cycle arrest, and it enhanced EBV eradication through activation of NF-KB/TNF-a signaling. The upregulation of SLC1A1, which promotes tumor progression in NKTCL, was negatively correlated with the expression of the tumor suppressor protein NKRF, and NKRF transcriptionally downregulated SLC1A1 expression by binding to its promoter.