Oncogenic Properties of NEAT1 in Prostate Cancer Cells Depend on the CDC5L-AGRN Transcriptional Regulation Circuit.

The long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been shown to regulate multiple cancer-related cellular activities including cell proliferation, apoptosis, and migration. In this study, we confirm that repression of NEAT1 induces DNA damage, disturbs the cell cycle, and arrests the proliferation of prostate cancer cells. By taking advantage of the prostate cancer tumor transcriptome profiles from The Cancer Genome Atlas, our data-mining pipeline identified a series of transcription factors (TF) whose regulatory activities on target genes depended on the level of NEAT1. Among them was putative TF CDC5L, which bound directly to NEAT1. Silencing NEAT1 in prostate cancer cells repressed the transcriptional activity of CDC5L, and RNA-seq and ChIP-seq analyses further revealed a handful of potential targets of CDC5L regulated by NEAT1 expression. One target of CDC5L, ARGN, mediated the strong phenotypic consequences of NEAT1 reduction, including DNA damage, cell-cycle dysregulation, and proliferation arrest. In summary, we have established the requirement of the CDC5L-AGRN circuit for the essential oncogenic role of NEAT1 in prostate cancer cells.Significance: An integrative methodology uncovers CDC5L-AGRN signaling as critical to the tumor-promoting function of long noncoding RNA NEAT1 in prostate cancer cells. Cancer Res; 78(15); 4138-49. ©2018 AACR. ©2018 American Association for Cancer Research.