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Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells.

ABSTRACT: Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death in vitro and in vivo. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances cellular survival through the phosphorylation-dependent inhibition of several pro-apoptotic proteins. Akt is an important negative regulator of GSK3beta, a kinase that has been shown to regulate apoptosis in response to various stimuli. In the present study, we investigated the role of GSK3beta in mediating the cytotoxic effects in MCF-7 breast cancer cells treated with trichostatin A (TSA), a prototype HDACI. We show that TSA induces Akt dephosphorylation in a PP1-dependent manner, resulting in activation of GSK3beta in MCF-7 cells. Similarly, knockdown of HDAC1 and-2 by small interfering RNA (siRNA) resulted in the dephosphorylation of Akt and GSK3beta. Selective inhibition of GSK3beta attenuated TSA induced cytotoxicity and resulted in enhanced proliferation following drug removal. Our findings identify GSK3beta as an important mediator of TSA-induced cytotoxicity in MCF-7 breast cancer cells.

SUBMITTER: Alao JP

PROVIDER: S-EPMC1592505 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells.

Alao John P JP Stavropoulou Alexandra V AV Lam Eric W-F EW Coombes R Charles RC

Molecular cancer 20061003

Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death in vitro and in vivo. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances ce ...[more]

PMID: 17018141

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Project description:BackgroundTrichostatin A (TSA), a potent inhibitor of histone deacetylases exhibits strong anti-tumor and growth inhibitory activities, but its mechanism(s) of action is not completely understood. Osteopontin (OPN) is a secreted glycoprotein which has long been associated with tumor metastasis. Elevated OPN expression in various metastatic cancer cells and the surrounding stromal cells often correlates with enhanced tumor formation and metastasis. To investigate the effects of TSA on OPN transcription, we analyzed a proximal segment of OPN promoter in cervical carcinoma cells.ResultsIn this paper, we for the first time report that TSA suppresses PMA-induced OPN gene expression in human cervical carcinoma cells and previously unidentified AP-1 transcription factor is involved in this event. Deletion and mutagenesis analyses of OPN promoter led to the characterization of a proximal sequence (-127 to -70) that contain AP-1 binding site. This was further confirmed by gel shift and chromatin immunoprecipitation (ChIP) assays. Western blot and reverse transcription-PCR analyses revealed that TSA suppresses c-jun recruitment to the OPN promoter by inhibiting c-jun levels while c-fos expression was unaffected. Silencing HDAC1 followed by stimulation with PMA resulted in significant decrease in OPN promoter activity suggesting that HDAC1 but not HDAC3 or HDAC4 was required for AP-1-mediated OPN transcription. TSA reduces the PMA-induced hyperacetylation of histones H3 and H4 and recruitment of RNA pol II and TFIIB, components of preinitiation complex to the OPN promoter. The PMA-induced expression of other AP-1 regulated genes like cyclin D1 and uPA was also altered by TSA. Interestingly, PMA promoted cervical tumor growth in mice xenograft model was significantly suppressed by TSA.ConclusionsIn conclusion, these findings provide new insights into mechanisms underlying anticancer activity of TSA and blocking OPN expression at transcriptional level by TSA may act as novel therapeutic strategy for the management of cervical cancer.

Dataset Information

Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells.

Publications

Role of glycogen synthase kinase 3 beta (GSK3beta) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells.

Similar Datasets

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