AbstractCells incurring oncogenic hits are often eliminated by cell death via built-in anti-cancer defense mechanisms, broadly termed as intrinsic tumor suppression (ITS). Identification of genetic modifiers of ITS-induced cell death would provide better understanding of inherent tumor-resistance and/or susceptibility. Using a Drosophila model of loss of a tumor suppressor-mediated epithelial tumorigenesis, here we show that perturbations in levels of stress-responsive nuclear long non-coding RNA (lncRNA) hsrω gene, promote epithelial tumorigenesis. Thus, while somatic clones with loss of a tumor suppressor, Lgl, are eliminated by JNK-induced cell death, lgl mutant somatic clones induced either in an hsrω loss-of-function heterozygous genetic background, or upon cell autonomous up- or down-regulation of hsrω in lgl somatic clones, override the JNK-mediated cell death and progress to full blown tumors. These tumors display deregulation of Hippo pathway as seen from a gain of downstream target of inhibition, Diap1, an inhibitor of cell death. We finally show that downregulation in sat III non-coding RNA, a functional analog of hsrω in humans, increases sensitivity of cancer cells to cytotoxic stress-induced cell death. lncRNA hsrω, therefore, constitutes a novel genetic modifier of ITS in Drosophila and of stress-induced cell death in human cancers.SummaryA long non-coding RNA, hsrω, is a novel regulator of JNK-mediated intrinsic tumor suppression in Drosophila.Highlightslgl clones induced in hsrω heterozygous loss-of-function genetic background escape intrinsic tumor suppression (ITS).Perturbation of hsrω in lgl mutant clones, too, leads to their escape from ITS.hsrω homeostasis required for JNK-dependent ITS.Human sat III, a functional analog of hsrω, confers stress-resistant to human cancer cells.
Long non-coding RNA tumor suppressor candidate 7 advances chemotherapy sensitivity of endometrial carcinoma through targeted silencing of miR-23b
