hTERT EXPRESSION IS REGULATED BY THE ACTIVATION OF HSF1

ZGAJNAR N; GALIGNIANA MD; LOTUFO C

Congreso; LXIII Reunión Anual de SAIC; 2018

Cancer cells achieve proliferative immortality by upregulatingtelomerase. hTERT is the catalytic subunit with reverse-transcriptaseactivity, which forms complexes with a template functionalRNA, Hsp90, p23, and other accessory proteins. Recently, wedemonstrated that two Hsp90-binding immunophilins, FKBP51and FKBP52, are overexpressed in cancer cells and associatedto hTERT. FKBP51 is also an antiapoptotic factor that undergoesnuclear-mitochondrial trafficking and binds to the hTERT?Hsp90nuclear heterocomplex in a peptidylprolyl-isomerase (PPIase)-independentmanner enhancing telomerase enzymatic. This effectis PPIase-dependent. hTERT nuclear localization is favored byFKBP52 via the cytoplasmic Hsp90?FKBP52?dynein retrotransportmachinery, and because FKBP52 anchors hTERT to nucleoskeletonstructures. In this study we analyzed the regulation of hTERTexpression and subcellular relocalization. The disruption of hTERTheterocomplex with radicicol (Hsp90 inhibitor) or by overexpressionof Hsp90-interacting TPR peptide, delocalizes nuclear hTERT to thecytoplasm. This Hsp90-free hTERT is degraded via proteasome unlessit is targeted to mitochondria, where it seems to complement theantiapoptotic effects of FKBP51. Oxidative stimuli (H2O2, arsenite,BSO, tert-butyl-hydroperoxide, etc.) also disengage hTERT fromnuclear structures favoring its nuclear export. Importantly, oxidativestress increases hTERT expression. Because high ionic strength,high glucose, heat-shock, etc. also show similar effect, we postulatedthat the HSF1 activation could be involved. This was confirmeddue to the lack of hTERT induction in HSF1-KO cells compared towild-type cells, and by the high basal expression of hTERT due tothe mere overexpression of HSF1, even in the absence of stimuli.It is concluded that overall expression level of hTERT depends onHSF1 activation, whereas its subcellular localization is commandedby Hsp90.