Hes-1 SUMOylation by protein inhibitor of activated STAT1 enhances the suppressing effect of Hes-1 on GADD45α expression to increase cell survival

Background: hairy and enhancer of split 1 (hes-1) is a transcriptional repressor that plays an important role in neuronal differentiation and development,but post-translational modifications of hes-1 are much less known. in the present study,we aimed to investigate whether hes-1 could be sumo-modified and identify the candidate sumo acceptors on hes-1. we also wished to examine the role of the sumo e3 ligase protein inhibitor of activated stat1 (pias1) in sumoylation of hes-1 and the molecular mechanism of hes-1 sumoylation. further,we aimed to identify the molecular target of hes-1 and examine how hes-1 sumoylation affects its molecular target to affect cell survival. results: in this study,by using hek293t cells,we have found that hes-1 could be sumo-modified and hes-1 sumoylation was greatly enhanced by the sumo e3 ligase pias1 at lys8,lys27 and lys39. furthermore,hes-1 sumoylation stabilized the hes-1 protein and increased the transcriptional suppressing activity of hes-1 on growth arrest and dna damage-inducible protein alpha (gadd45α) expression. overexpression of gadd45α increased,whereas knockdown of gadd45αα expression decreased cell apoptosis. in addition,h2o2 treatment increased the association between pias1 and hes-1 and enhanced the sumoylation of hes-1 for endogenous protection. overexpression of hes-1 decreased h2o2-induced cell death,but this effect was blocked by transfection of the hes-1 triple sumo-mutant (hes-1 3kr). overexpression of pias1 further facilitated the anti-apoptotic effect of hes-1. moreover,hes-1 sumoylation was independent of hes-1 phosphorylation and vice versa. conclusions: the present results revealed,for the first time,that hes-1 could be sumo-modified by pias1 and gadd45α is a novel target of hes-1. further,hes-1 sumoylation mediates cell survival through enhanced suppression of gadd45α expression. these results revealed a novel role of hes-1 in addition to its involvement in notch signaling. they also implicate that sumoylation could be an important posttranslational modification that regulates cell survival. © 2014 chiou et al.; licensee biomed central ltd.