Acetylation of the C Terminus of Ku70 by CBP and PCAF Controls Bax-Mediated Apoptosis

Cohen, Haim Y.; Lavu, Siva; Bitterman, Kevin J.; Hekking, Brian; Imahiyerobo, Thomas; Miller, Christine; Frye, Roy A.; Ploegh, Hidde L.; Kessler, Benedikt M.; Sinclair, David A.

doi:10.1016/s1097-2765(04)00094-2

Cited by 548 publications

(572 citation statements)

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“…Treatment with MS-275 alone causes Ku70 acetylation and Bax activation, consistent with previous reports that acetylation of Ku70 disrupts its interaction with Bax (Cohen et al, 2004;Subramanian et al, 2005), whereas monotherapy with Doxorubicin triggers p53 acetylation and accumulation. Both compounds cooperate to trigger the binding of p53 to Bax and p53-dependent Bax activation, resulting in loss of mitochondrial membrane potential, cytochrome c release and caspase-dependent apoptotic cell death.…”

supporting

confidence: 90%

“…First, HDACI cause accumulation of acetylated histones, which favors an open state of the chromatin, thereby facilitating gene transcription (Bolden et al, 2006;Xu et al, 2007). More recently, HDACI have also been shown to trigger acetylation of a number of non-histone proteins, for example the DNA repair protein Ku70, which reduces its DNA repair capacity as well as its interaction with the proapoptotic protein Bax (Cohen et al, 2004;Subramanian et al, 2005;Chen et al, 2007). The anticancer effects of HDACI have been largely attributed to their ability to trigger programmed cell death (apoptosis) (Bolden et al, 2006).…”

mentioning

confidence: 99%

“…As the acetylation status of Ku70 has been reported to also affect its interaction with Bax (Cohen et al, 2004), we next assessed Bax activation. Interestingly, MS-275 and Doxorubicin or VP-16 cooperated to trigger Bax conformational change (Figure 2b), which was also detected in the presence of the caspase inhibitor z-VADfmk (Supplementary Figure 3), demonstrating that it occurred before caspase activation.…”

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confidence: 99%

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Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

et al. 2011

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Despite aggressive therapies, the prognosis of children with high-risk medulloblastoma is still poor, thus underscoring the need to develop novel treatment strategies. Here, we report that histone deacetylase inhibitors (HDACI), that is, MS-275, valproic acid or SAHA, provide a novel strategy for sensitization of medulloblastoma to DNA-damaging drugs such as Doxorubicin, VP16 and Cisplatin by promoting p53-dependent, mitochondrial apoptosis. Mechanistic studies reveal that single-agent treatment with MS-275 causes acetylation of the non-histone protein Ku70, an event reported to release Bax from Ku70, whereas DNAdamaging drugs trigger p53 acetylation and accumulation. Combined treatment with MS-275 and Doxorubicin or VP16 cooperates to promote binding of p53 to Bax and p53-dependent Bax activation, resulting in enhanced loss of mitochondrial membrane potential, cytochrome c release and caspase-dependent apoptosis. Overexpression of Bcl-2 almost completely abolishes the MS-275-mediated chemosensitization, underlining the importance of the mitochondrial pathway for inducing apoptosis. Also, MS-275 cooperates with chemotherapeutics to inhibit long-term clonogenic survival. Most importantly, MS-275 increases chemotherapeutic drug-induced apoptosis in primary medulloblastoma samples, and cooperates with Doxorubicin to suppress medulloblastoma growth in an in vivo model, which underscores the clinical relevance of the findings. Thus, HDACI such as MS-275 present a promising approach for chemosensitization of medulloblastoma by enhancing mitochondrial apoptosis in a p53-dependent manner. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma.

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Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

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“…In its deacetylated form (maintained by several HDACs), Ku70 keeps BAX away from the mitochondrion and protects cells from apoptosis. When the cell is stressed, HATs acetylate Ku70, leading to dissociation of the complex and translocation of BAX to the mitochondria, where it activates the apoptotic programme 27,28 .…”

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confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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“…A recent report shows that HDAC inhibitors increase acetylation of Ku70 and abolish its ability to suppress Bax-mediated apoptosis. 22 This suggests that the mitochondria-mediated death signals may be crucial for HADC inhibitor-mediated apoptosis. Based on this idea, we have been attempting to identify novel HDAC inhibitor-inducible proapoptotic genes.…”

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confidence: 99%

Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis

et al. 2005

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Histone deacetylase (HDAC) inhibitors modify transcription of selected genes and eventually induce apoptosis. However, molecular mechanisms for their proapoptotic activity remain unclear. We here demonstrate that HDAC inhibitors FK228 and CBHA preferentially upregulated the BH3-only protein Bmf in a broad range of cancer cells. In contrast, HDAC1 overexpression distinctly reduced Bmf expression. FK228 induced histones H3 and H4 acetylation at Bmf promoter region, but not at its 3 0 region, suggesting that histone hyperacetylation causes Bmf transcriptional activation. Knockdown of Bmf transcripts rescued cells from FK228 or CBHA-induced cell death, disruption of mitochondrial membrane potential (DWm) and DNA fragmentation. Taken together, FK228 and CBHA activate Bmf transcription by histone hyperacetylation at its promoter region, and inhibition of this action decreased their proapoptotic activity, thereby highlighting a central role of Bmf in HDAC inhibitor-mediated apoptosis.

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Acetylation of the C Terminus of Ku70 by CBP and PCAF Controls Bax-Mediated Apoptosis

Cited by 548 publications

References 53 publications

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis

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