Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells

Yan, Gai; Eller, Mark S.; Elm, Courtney M.L.; Larocca, Cecilia; Ryu, Byungwoo; Panova, Izabela P.; Dancy, Beverley M.; Bowers, Erin M.; Meyers, David J.; Lareau, Lisa; Cole, Philip A.; Taverna, Sean D.; Alani, Rhoda M.

doi:10.1038/jid.2013.187

Cited by 96 publications

(82 citation statements)

References 40 publications

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“…Compared to acetylation levels at time zero (G 1 -arrested cells), we observed an initial peak of ADA3 acetylation at 4 h followed by a second peak that persisted throughout S and G 2 /M phases. Notably, these dynamic changes in ADA3 acetylation are consistent with previous reports of increases in GCN5 protein levels as cells enter the S phase (33) and a requirement of the HAT activity of p300 for G 1 -S transition (34)(35)(36)(37)(38). Taken together, our results demonstrate that ADA3 acetylation is cell cycle dependent and raised the possibility that acetylation of ADA3 regulates its function in cell cycle progression.…”

Section: Ada3 Acetylation Levels Change During Cell Cycle Progressionsupporting

confidence: 81%

“…Such dynamic regulation during cell cycle progression further supports the functional role of ADA3 acetylation, suggesting regulation at the levels/activities of HATs/HDACs targeting the acetylation/deacetylation of ADA3. The transient earlier peak and more sustained delayed ADA3 acetylation during cell cycle progression may reflect the relative activities of GCN5 and p300, a possibility consistent with the reported increase in GCN5 levels from G 1 to early S phase (33) and the requirement for p300 HAT activity for progression through S phase (34)(35)(36)(37)(38). If established in future studies, such a scheme will support distinct roles for GCN5/ PCAF-versus p300-mediated acetylation of ADA3.…”

Section: Discussionsupporting

confidence: 57%

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Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

Mohibi

Srivastava

Bele

et al. 2016

Molecular and Cellular Biology

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Alteration/deficiency in activation 3 (ADA3) is an essential component of specific histone acetyltransferase (HAT) complexes. We have previously shown that ADA3 is required for establishing global histone acetylation patterns and for normal cell cycle progression (S. Mohibi et al., J Biol Chem 287:29442-29456, 2012, http://dx.doi.org/10.1074/jbc.M112.378901). Here, we report that these functional roles of ADA3 require its acetylation. We show that ADA3 acetylation, which is dynamically regulated in a cell cycle-dependent manner, reflects a balance of coordinated actions of its associated HATs, GCN5, PCAF, and p300, and a new partner that we define, the deacetylase SIRT1. We use mass spectrometry and site-directed mutagenesis to identify major sites of ADA3 acetylated by GCN5 and p300. Acetylation-defective mutants are capable of interacting with HATs and other components of HAT complexes but are deficient in their ability to restore ADA3-dependent global or locus-specific histone acetylation marks and cell proliferation in Ada3-deleted murine embryonic fibroblasts (MEFs). Given the key importance of ADA3-containing HAT complexes in the regulation of various biological processes, including the cell cycle, our study presents a novel mechanism to regulate the function of these complexes through dynamic ADA3 acetylation.A lteration/deficiency in activation 3 (ADA3) protein is a conserved component of key chromatin-modifying complexes that contain either GCN5 or PCAF histone acetyl transferases (HATs), such as SAGA (Spt/Ada/Gcn5) in yeast, ATAC (ADA2a-containing complex), STAGA (SPT3/TAFII31/GCN5 acetyltransferase), and TFTC (TATA binding protein free-TAF containing complex) in metazoans (1-7). Within these complexes, ADA3 associates with GCN5 and ADA2 to form the HAT module. ADA3 has also been shown to associate with p300, the most well-defined HAT of mammalian systems (8, 9). ADA3 is essential for the HAT activity of p300-and GCN5-containing HAT complexes toward histones (10-14) as well as of nonhistone proteins, such as p53 and ␤-catenin (15, 16).Although strongly implicated in the regulation of HAT activity of ADA3-containing complexes, additional functions for ADA3 have been reported. For example, we identified ADA3 as a novel human papillomavirus E6 oncoprotein-binding protein (17), and additional studies revealed that ADA3 binds to nuclear hormone receptors, such as estrogen receptor and retinoid acid receptor, and enhances their transcriptional activation function (8,(18)(19)(20)(21). Recent studies have identified an essential role of ADA3 in normal cell cycle progression and maintenance of genomic stability (5, 13, 22, 23).Whether ADA3's role in these processes is merely a passive structural one or is actively regulated is unknown. Posttranslational modification represents one potential mechanism to regulate ADA3 function, and in fact yeast ADA3 was found to be modified by acetylation (24). Consistent with this idea, we observed that human ADA3 is also acetylated in vitro by its interacting HAT p300 (13). H...

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Section: Ada3 Acetylation Levels Change During Cell Cycle Progressionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 57%

Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

Mohibi

Srivastava

Bele

et al. 2016

Molecular and Cellular Biology

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“…S4A). Earlier studies have claimed that doxorubicin was effective at killing colorectal cancer cells (31) and that C646 was able to inhibit their growth (32). Although our cell viability assays hinted a slight p53-dependent protection of HCT116 cells by C646 against doxorubicin ( Fig.…”

Section: Addressing the Safety Concerns Of C646mentioning

confidence: 47%

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

et al. 2017

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Chemotoxicity due to unwanted p53 activation in the bone marrow remains an unmet clinical challenge. Doxorubicin, a firstline chemotherapy drug, often causes myelosuppression in patients, thus limiting its effectiveness. In this study, we discovered that C646, a reversible p300 inhibitor, downregulates p53 transcription and selectively protects noncancerous cells from p53-dependent apoptosis. C646 treatment blocked acetylation of specific lysine residues that regulate p53 activity. Exploitation of differential p53 genetic backgrounds between human hematopoietic and colorectal cancer cells improved the therapeutic index of doxorubicin with C646 cotreatment. C646 administration in mice afflicted with p53-mutant tumors protected them from doxorubicin-induced neutropenia and anemia while retaining antitumor efficacy. We deduce that temporary and reversible inhibition of p53 acetylation in cancer subjects, especially those with p53-mutant tumors, may protect them from severe chemotoxicity while allowing treatment regimens to effectively proceed.Cancer Res; 77(16); 4342-54. Ó2017 AACR.

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“…Previous studies have reported that a combination of HDACIs, such as TSA combined with curcumin, produced significant antiproliferative and apoptotic effects compared with either agent alone. 40 The combination of quercetin and TSA significantly increased the cytotoxic effect in A549 cells, 41 whereas that of TSA and PdNPs produced a significant inhibitory effect on cell survival and HDAC activity in HeLa cells. In order to determine the correlation between cell viability and HDAC activity, we first evaluated the combinatorial effect of TUB-A and PdNPs on cell viability and HDAC activity in MDA-MB-231 human breast cancer cells.…”

Section: Results and Discussion Synthesis And Characterization Of Pdnpsmentioning

confidence: 99%

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

Yuan¹,

Peng²,

Gurunathan³

2017

IJN

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Background Breast cancer is the most common malignant disease that occurs in women. Histone deacetylase (HDAC) inhibition has recently emerged as an effective and attractive target for the treatment of cancer. The aim of this study was to investigate the efficacy of a combined treatment of tubastatin A (TUB-A) and palladium nanoparticles (PdNPs) against MDA-MB-231 human breast cancer cells using two different cytotoxic agents that work by two different mechanisms, thereby decreasing the probability of chemoresistance in cancer cells and increasing the efficacy of toxicity, to provide efficient therapy for advanced stage of cancer without any undesired side effects. Methods PdNPs were synthesized using a novel biomolecule called R-phycoerythrin and characterized using various analytical techniques. The combinatorial effect of TUB-A and PdNPs was assessed by various cellular and biochemical assays and also by gene expression analysis. Results The biologically synthesized PdNPs had an average size of 25 nm and were spherical in shape. Treatment of MDA-MB-231 human breast cancer cells with TUB-A or PdNPs showed a dose-dependent effect on cell viability. The combination of 4 μM TUB-A and 4 μM PdNPs had a significant inhibitory effect on cell viability compared with either TUB-A or PdNPs alone. The combinatorial treatment also had a more pronounced effect on the inhibition of HDAC activity and enhanced apoptosis by regulating various cellular and biochemical changes. Conclusion Our results suggest that there was a strong synergistic interaction between TUB-A and PdNPs in increasing apoptosis in human breast cancer cells. These data provide an important preclinical basis for future clinical trials on this drug combination. This combinatorial treatment increased therapeutic potentials, thereby demonstrating a relevant targeted therapy for breast cancer. Furthermore, we have provided the first evidence for the combinatorial effect and mechanism of toxicity of TUB-A and PdNPs in human breast cancer cells. The novelties of the study were identification of a combination therapy that consists of suitable therapeutic molecules that kill cancer cells and also exploration of two different possible mechanisms involved to reduce chemoresistance in cancer cells.

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Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells

Cited by 96 publications

References 40 publications

Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

Inhibiting p53 Acetylation Reduces Cancer Chemotoxicity

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

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