Abstract LB448: Unveiling novel type of cell death caused by depletion of lncRNA <i>JUNI</i>

Abstract Cellular proliferation and cell death are crucial for the sustenance of organismal wellbeing. Cancer cells evade most of the apoptotic and non-apoptotic cellular death pathways to survive and proliferate. In the last two decades, extensive research has demonstrated the involvement of various long non-coding RNAs (lncRNAs) in cancer development and progression. One such lncRNA is JUNI (LINC01135, JUN-DT), a stress-induced lncRNA upregulated under genotoxic stress, such as exposure to UV irradiation and chemotherapeutic drugs. JUNI is a primate-specific gene and induces the activity of the transcription factor and oncogene c-Jun. Depletion of JUNI sensitizes cancer cells to chemotherapeutic agents, thereby, reducing their survival. However, JUNI’s role in the survival of cancer cells is poorly understood.In our investigation, using melanoma and cervical adenocarcinoma cell lines, we identified and characterized a novel form of cell death caused by depletion of JUNI in cancer cells, even without the exposure to stress. The cell death exhibited a morphology distinct to any previously known cell death types. We showed that silencing of JUNI for 96 hours leads to up to 40-60% cell death in various cell types. Silencing for about two weeks reduces the survival to 20-25% relative to unsilenced cells. The effects of JUNI on cellular survival are more significant than the effects of its regulated gene c-Jun, whose knockdown leads to up to 40% cell death, 96 hours post-knockdown. Silencing of c-Jun for up to two weeks resulted in half the cell death caused by JUNI’s silencing. Transfecting JUNI-silenced cells with c-Jun expression vector improved the survival partially. These results suggest JUNI’s effect on cellular survival to be mostly independent of c-Jun activity. A morphological characterization of JUNI-induced cell death using high-magnification fluorescent microscopy revealed a novel cell death phenotype which does not conform to any known cell death type.Our study reveals the importance of JUNI for the survival of chemotherapy-treated and naïve cancer cells, which, in its absence, die via novel cell death type. Our investigation provides new insights in lncRNA biology, highlighting JUNI as a prospective therapeutic target, potentially bridging the gap between fundamental research and clinical oncology. Citation Format: Isha Soni, Vikash Kumar, Eitan Shaulian. Unveiling novel type of cell death caused by depletion of lncRNA JUNI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB448.