Lnc-RAINY regulates genes involved in radiation susceptibility through DNA:DNA:RNA triplex-forming interactions and has tumor therapeutic potential in lung cancers

Lung cancer is the leading cause of cancer related deaths worldwide. Unfortunately, radiation resistance remains a major problem facing lung cancer patients. Recently, we identified a group of long non-coding RNAs (lncRNAs) known as linc-SPRY3 RNAs, expressed on the Y-chromosome, which play a role in radiation sensitivity by decreasing tumor burden <i>in vitro</i> and <i>in vivo</i> after radiation. In this study, we found that the linc-SPRY3 RNAs are one large lncRNA that we named <i>Ra</i>diation <i>In</i>duced <i>Y</i>-chromosome linked long non-coding RNA (lnc-RAINY). Through ATAC-seq and immunoprecipitation experiments, we show that lnc-RAINY interacts with DNA in a triple helix to induce chromatin remodeling and gene expression. We also identified that lnc-RAINY regulates CDC6 and CDC25A expression affecting senescence induction, cell migration patterns, and cell cycle regulation. Furthermore, the administration of Lnc-RAINY encapsulated in FDA-approved nanoparticles into a lung cancer patient-derived xenograft model dramatically reduces tumor progression demonstrating therapeutic potential.