LONG NON-CODING RNAs FROM TELOMERES RESPOND TO OXIDATIVE STRESS AND EPITHELIAL-MESENQUIMAL TRANSITION (EMT)

GALIGNIANA NATALIA MARICEL; LLORENS MARÍA CANDELARIA; VAGLIENTI MARIA VICTORIA; CABANILLAS ANA MARIA; PIWIEN-PILIPUK, GRACIELA

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2018

Sociedad Argentina de Investigación Clínica

Long non-coding RNAs transcribed from telomeres, known as TERRA (telomeric repeatcontaining RNA), are associated with telomere and genome stability. TERRA expression is elevated in human cancer tissues, however little is known about their function. Oxidative stress damages biomolecules and activates signaling cascades involved in cell proliferation, apoptosis, and metastasis. Since telomeres are prone to oxidative damage leading to their dysfunction, our objective is to characterize TERRA expression in oxidative stress, the mechanisms involved and its relevance in EMT. H2O2 induces TERRA expression in HEK-293T cells, and is prevented by antioxidant treatment. It was reported ROS are increased in brown (BAT) but not in white adipose tissue of mice exposed to cold. Importantly, we found increased TERRAs only in BAT of mice exposed to cold. In HEK-293T cells exposed to H2O2, ChIP shows that chromatin landscape is modified favoring telomere transcription. TERRAs interact with HP1α/γ, both proteins found recruited to subtelomeres. Since HP1γ interacts with transcriptional machinery, TERRAs may stimulate their own expression by recruiting HP1γ to subtelomeres. TERRA induction is lost 1-2h after removal of H2O2 from culture medium, suggesting they have protective functions. This is supported by rapid increase of TERRA upon a second H2O2 challenge. PKA inhibitor H89 blocks the increase of TERRA induced by H2O2, suggesting that PKA controls TERRA induction. Treatment of cells with drugs that disturb cytoskeleton integrity or growing cells on surfaces of different stiffness that generate differential cytoskeleton tension also modifies TERRA levels. In fact, cytoskeleton rearrangements of EMT transformed NMuMG cells associate with higher TERRAs and lack response to H2O2, mimicking what occurs in T47D breast cancer cells that exhibit telomere dysfunction evidenced by confocal microscopy. In summary, we show that TERRAs are induced in response to oxidative stress and may be induced during EMT, being potentially novel early markers of cancer progression.