HSP25 down-regulation enhanced p53 acetylation by dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis

Abstract

Heat shock proteins (HSPs) play important roles in cellular stress resistance. Previous reports had already suggested that HSP27 played multiple roles in preventing doxorubicin-induced cardiotoxicity. Although HSP25 might have biological functions similar to its human homolog HSP27, the mechanism of HSP25 is still unclear in doxorubicin-induced cardiomyocyte apoptosis. To investigate HSP25 biological function on doxorubicin-induced apoptosis, flow cytometry was employed to analyze cell apoptosis in over-expressing HSP25 H9c2 cells in presence of doxorubicin. Unexpectedly, the H9c2 cells of over-expressing HSP25 have no protective effect on doxorubicin-induced apoptosis. Moreover, no detectable interactions were detected by coimmunoprecipitation between HSP25 and cytochrome c, and HSP25 over-expression failed in preventing cytochrome c release induced by doxorubicin. However, down-regulation of endogenous HSP25 by a specific small hairpin RNA aggravates apoptosis in H9c2 cells. Subsequent studies found that HSP25, but not HSP90, HSP70, and HSP20, interacted with SIRT1. Knockdown of HSP25 decreased the interaction between SIRT1 and p53, leading to increased p53 acetylation on K379, up-regulated pro-apoptotic Bax protein expression, induced cytochrome c release, and triggered caspase-3 and caspase-9 activation. These findings indicated a novel mechanism by which HSP25 regulated p53 acetylation through dissociation of SIRT1 from p53 in doxorubicin-induced H9c2 cell apoptosis.

Liraglutide repairs the infarcted heart: The role of the SIRT1/Parkin/mitophagy pathway

“…NAD-dependent protein deacetylase sirtuin 1 (SIRT1) is one of the seven mammalian homologs (SIRT1-SIRT7) of the yeast silent information regulator 2 ( 25 ). SIRT1 is an NAD + -dependent protein deacetylase which has been reported to serve a number of roles in cells, including longevity, apoptosis, DNA repair, inflammation and mitochondrial regulation ( 26 – 28 ). The regulatory effect of SIRT1 on the activation of mitophagy has gained attention, although the underlying mechanisms have not been completely elucidated.…”

Heat-shock protein 27 (HSP27, HSPB1) is synthetic lethal to cells with oncogenic activation of MET, EGFR and BRAF

“…Here, we show however that the protective effect might occur also earlier in the mitochondrial pathway of apoptosis, by blocking mitochondrial permeabilization. This could be due to the known ability of HSP27 to stabilize directly or indirectly upstream molecules such as AKT and BAX (Arrigo, ; Havasi et al ., ; Zhang et al ., ).…”

Histone H3K9 acetylation influences growth characteristics of goat adipose-derived stem cells in vitro

“…For example, Adriamycin treatment of H9c2 cells downregulates heat shock protein 25 and weakens the interaction between SIRT1 and P53. This results in acetylation of the lysine residue at position 379 of P53, and activation of P53 transcription, thereby increasing BAX protein expression and inducing apoptosis (Zhang et al, 2016). Treatment of RKO cells, a human colon cancer line, with the HDACI CG200745 increases acetylation of the lysine at position 382 of P53, promotes P53-dependent gene transcription, enhances expression of the P53 target genes MDM2 and P21, and induces cell death (Oh et al, 2012).…”