CONICET | Buscador de Institutos y Recursos Humanos

Telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA expression is elevated in human cancer tissues, however little is known about their regulation in cancer progression. We have shown that TERRAs are induced by oxidative stress that alters microtubule integrity. TERRA induction was mimicked by treatment of cells with either, the microtubule-disrupting agent colcemidor taxol, a microtubule-stabilizing drug, suggesting that TERRA induction is delicately regulated by mechanotransduction. During epithelial-mesenchymal transition (EMT), epithelial cells reorganize their cytoskeleton as they transition into mesenchymal cells. Thus, the aim of our study was to characterize TERRA expression during this process. The mouse mammary epithelial cells NMuMG undergo EMT following TGFβ1 stimulation. Transdifferentiation of NMuMG after 96h treatment with 5ng/ml TGFβ1 induced a change in theirmorphology from an epithelial to an elongated, fibroblastic phenotype; reported to result from microfilament reorganization. This change correlated with decreased expression of the epithelial marker E-cadherin and increased expression of mesenchymal markers ZEB1, ZEB2, SNAIL, and SLUG as assessed by Western blot, demonstrating the occurrence of EMT. Importantly, qPCR analysisshowed an induction of TERRAs during the EMT of NMuMG, result in line with our hypothesis that TERRA expression can be regulated by cytoskeleton remodeling. To further explore its relevance in EMT, we measured TERRA levels after treating NMuMG and transdifferentiated NMuMG cells with 0,5mM H2O2. NMuMG undergo TERRAinduction shortly after H2O2 treatment. In contrast, TERRA induction was abrogated in transdifferentiated NMuMG, suggesting that changes in the cytoskeleton undergone during EMT altered TERRA regulation in response to H2O2. In summary, we show for the first time that TERRAs may be induced during EMT and they could be potentially novel early markers of cancer progression.