Long non-coding RNA KIKAT/LINC01061 as a novel epigenetic regulator that relocates KDM4A on chromatin and modulates viral reactivation

Abstract

KDM4A is a histone lysine demethylase that has been described as an oncogene in various types of cancer. The importance of KDM4A-mediated epigenetic regulation in tumorigenesis is just emerging. Here, by using Kaposi’s sarcoma associated herpesvirus (KSHV) as a screening model, we identified 6 oncogenic virus-induced long non-coding RNAs (lncRNAs) with the potential to open chromatin. RNA immunoprecipitation revealed KSHV-induced KDM4A-associated transcript (KIKAT)/LINC01061 as a binding partner of KDM4A. Integrated ChIP-seq and RNA-seq analysis showed that the KIKAT/LINC01061 interaction may mediate relocalization of KDM4A from the transcription start site (TSS) of the AMOT promoter region and transactivation of AMOT, an angiostatin binding protein that regulates endothelial cell migration. Knockdown of AMOT diminished the migration ability of uninfected SLK and iSLK-BAC16 cells in response to KIKAT/LINC01061 overexpression. Thus, we conclude that KIKAT/LINC01061 triggered shifting of KDM4A as a potential epigenetic mechanism regulating gene transactivation. Dysregulation of KIKAT/LINC01061 expression may represent a novel pathological mechanism contributing to KDM4A oncogenicity.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…One of them was ATOM , which encodes angiomotin, a protein that promotes cell migration and angiogenesis. In accordance, overexpression of KIKAT/LINC01061 in SLK cells induced cell migration [ 317 ]. Hence, KSHV-induced expression of KIKAT/LINC01061 may play a role in KSHV’s pathogenicity.…”

Aid or Antagonize: Nuclear Long Noncoding RNAs Regulate Host Responses and Outcomes of Viral Infections

“…The KSHV-lytic protein (K-Rta) induces the expression of a cellular lncRNA KIKAT/LINC01061 (KSHV-Induced KDM4A-Associated Transcript) [ 68 ]. Yang et al showed that KIKAT interacts with a histone lysine demethylase (KDM4A) and re-localizes KDM4A from the transcription start site (TSS) of the Angiomotin (AMOT) gene.…”

“…Yang et al showed that KIKAT interacts with a histone lysine demethylase (KDM4A) and re-localizes KDM4A from the transcription start site (TSS) of the Angiomotin (AMOT) gene. The KIKAT -mediated relocation of KDM4A increased the AMOT transcription and angiomotin-dependent cell migration, thus implicating its role in angiogenesis in Kaposi’s sarcoma [ 68 ]. KIKAT was also shown to enhance KSHV reactivation.…”

“…KIKAT was also shown to enhance KSHV reactivation. While KDM4A was shown to regulate KSHV replication [ 155 , 156 ], its binding on the KSHV genome was not impacted by KIKAT [ 68 ].…”

“…In addition, stimulating cells by cytokines, such as IFN-I [ 65 ] and TNF-α [ 66 ], induces differential expressions of lncRNAs. Viral infections, including specific viral proteins can upregulate the expression of stress-induced and other lncRNAs [ 67 , 68 ]. Thus, the transcriptome of virus-infected cells presents an opportunity to discover and characterize novel lncRNAs that may play a significant role in cellular defense, immune response, and viral propagation.…”