Long non-coding RNAs from telomeres respond to oxidative stress and epithelial-mesenquimal transition (EMT)

GALIGNIANA, NATALIA MARICEL; LLORENS, M. CANDELARIA; CHARÓ, NANCY L; VAGLIENTI, MARIA V.; CABANILLAS, ANA M.; PIWIEN-PILIPUK, GRACIELA

Mar del Plata

Congreso; Reunión Conjunta SAIC SAI SAFIS 2018; 2018

SAIC SAI SAFIS

Long non-coding RNAs transcribed from telomeres,known as TERRA (telomeric repeat-containing RNA), areassociated with telomere and genome stability. TERRAexpression is elevated in human cancer tissues, howeverlittle is known about their function. Oxidative stressdamages biomolecules and activates signaling cascadesinvolved in cell proliferation, apoptosis, and metastasis.Since telomeres are prone to oxidative damage leadingto their dysfunction, our objective is to characterizeTERRA expression in oxidative stress, the mechanismsinvolved and its relevance in EMT. H2O2 induces TERRAexpression in HEK-293T cells, and is prevented byantioxidant treatment. It was reported ROS are increasedin brown (BAT) but not in white adipose tissue of miceexposed to cold. Importantly, we found increased TERRAsonly in BAT of mice exposed to cold. In HEK-293Tcells exposed to H2O2, ChIP shows that chromatinlandscape is modified favoring telomere transcription.TERRAs interact with HP1α/γ, both proteins found recruitedto subtelomeres. Since HP1γ interacts with transcriptionalmachinery, TERRAs may stimulate their ownexpression by recruiting HP1γ to subtelomeres. TERRAinduction is lost 1-2h after removal of H2O2 from culturemedium, suggesting they have protective functions. Thisis supported by rapid increase of TERRA upon a secondH2O2 challenge. PKA inhibitor H89 blocks the increaseof TERRA induced by H2O2, suggesting that PKA controlsTERRA induction. Treatment of cells with drugs thatdisturb cytoskeleton integrity or growing cells on surfacesof different stiffness that generate differential cytoskeletontension also modifies TERRA levels. In fact, cytoskeletonrearrangements of EMT-transformed NMuMGcells associate with higher TERRAs and lack responseto H2O2, mimicking what occurs in T47D breast cancercells that exhibit telomere dysfunction evidenced by confocalmicroscopy. In summary, we show that TERRAs areinduced in response to oxidative stress and may be inducedduring EMT, being potentially novel early markersof cancer progression.