Abstract
SAHA is a class I HDAC/HDAC6 co-inhibitor and an autophagy inducer currently undergoing clinical investigations in breast cancer patients. However, the molecular mechanism of action of SAHA in breast cancer cells remains unclear. In this study, we found that SAHA is equally effective in targeting cells of different breast cancer subtypes and tamoxifen sensitivity. Importantly, we found that down-regulation of survivin plays an important role in SAHA-induced autophagy and cell viability reduction in human breast cancer cells. SAHA decreased survivin and XIAP gene transcription, induced survivin protein acetylation and early nuclear translocation in MCF7 and MDA-MB-231 breast cancer cells. It also reduced survivin and XIAP protein stability in part through modulating the expression and activation of the 26S proteasome and heat-shock protein 90. Interestingly, targeting HDAC3 and HDAC6, but not other HDAC isoforms, by siRNA/pharmacological inhibitors mimicked the effects of SAHA in modulating the acetylation, expression, and nuclear translocation of survivin and induced autophagy in MCF7 and MDA-MB-231 cancer cells. Targeting HDAC3 also mimicked the effect of SAHA in up-regulating the expression and activity of proteasome, which might lead to the reduced protein stability of survivin in breast cancer cells. In conclusion, this study provides new insights into SAHA's molecular mechanism of actions in breast cancer cells. Our findings emphasize the complexity of the regulatory roles in different HDAC isoforms and potentially assist in predicting the mechanism of novel HDAC inhibitors in targeted or combinational therapies in the future.
Highlights
HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Trichostatin A (TSA), have been shown to exhibit pleiotropic anticancer activities in many preclinical and clinical investigations of human cancers (Vigushin et al, 2001; Kelly et al, 2003; Roh et al, 2004; Condorelli et al, 2008)
These results indicate that SAHA, at the tested concentrations, did function normally at the molecular level and induced autophagy in both MCF7 and MDA-MB-231 cells
Cleavage of caspase-3 and PARP, which are molecular markers for caspase3 activation, was only observed in the pro-caspase-3 expressing MDA-MB-231 cells treated with high concentration (2x IC50) of SAHA (Figure 1A), suggesting that caspase-3 activation might only play a role in the cell viability reduction induced by SAHA at high concentrations but not in moderate-to-low concentrations
Summary
HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Trichostatin A (TSA), have been shown to exhibit pleiotropic anticancer activities in many preclinical and clinical investigations of human cancers (Vigushin et al, 2001; Kelly et al, 2003; Roh et al, 2004; Condorelli et al, 2008). Survivin is a well-known member of the inhibitor-ofapoptosis proteins (IAPs) family It regulates mitosis and inhibits both caspase-dependent and -independent apoptosis in cancer cells (Li et al, 1998; Tamm et al, 1998; Cheung et al, 2010; Coumar et al, 2013). Our previous study revealed that even though survivin is an inhibitor of apoptosis, targeting survivin by small molecule inhibitor or by siRNA induces autophagy and autophagic cell death in breast cancer cells regardless of the endogenous expression of p53 and caspase-3 (Cheng et al, 2015). Survivin is traditionally classified as an apoptosis inhibitor; the role of survivin in SAHA-induced autophagy and autophagic cell death in cancer cells has seldom been investigated
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