hTERT EXPRESSION IS REGULATED BY THE ACTIVATION OF HSF1

CECILIA M. LOTUFO, NADIA R. ZGAJNAR, MARIO D. GALIGNIANA

Congreso; LXIII Reunión Anual de SAIC; 2018

Cancer cells achieve proliferative immortality by upregulating telomerase. hTERT is the catalytic subunit with reverse-transcriptase activity, which forms complexes with a template functional RNA, Hsp90, p23, and other accessory proteins. Recently, we demonstrated that two Hsp90-binding immunophilins, FKBP51 and FKBP52, are overexpressed in cancer cells and associated to hTERT. FKBP51 is also an antiapoptotic factor that undergoes nuclear-mitochondrial trafficking and binds to the hTERT?Hsp90 nuclear heterocomplex in a peptidylprolyl-isomerase (PPIase)-independent manner enhancing telomerase enzymatic. This effect is PPIase-dependent. hTERT nuclear localization is favored by FKBP52 via the cytoplasmic Hsp90?FKBP52?dynein retrotransport machinery, and because FKBP52 anchors hTERT to nucleoskeleton structures. In this study we analyzed the regulation of hTERT expression and subcellular relocalization. The disruption of hTERT heterocomplex with radicicol (Hsp90 inhibitor) or by overexpression of Hsp90-interacting TPR peptide, delocalizes nuclear hTERT to the cytoplasm. This Hsp90-free hTERT is degraded via proteasome unless it is targeted to mitochondria, where it seems to complement the antiapoptotic effects of FKBP51. Oxidative stimuli (H2O2, arsenite, BSO, tert-butyl-hydroperoxide, etc.) also disengage hTERT from nuclear structures favoring its nuclear export. Importantly, oxidative stress increases hTERT expression. Because high ionic strength, high glucose, heat-shock, etc. also show similar effect, we postulated that the HSF1 activation could be involved. This was confirmed due to the lack of hTERT induction in HSF1-KO cells compared to wild-type cells, and by the high basal expression of hTERT due to the mere overexpression of HSF1, even in the absence of stimuli. It is concluded that overall expression level of hTERT depends on HSF1 activation, whereas its subcellular localization is commanded by Hsp90.