Histone acetyltransferase inhibitors block neuroblastoma cell growth in vivo

Gajer, Julia M.; Furdas, Silviya D.; Gründer, Albert; Gothwal, Monika; Heinicke, Ulrike; Keller, K.; Colland, Frédéric; Fulda, Simone; Pahl, Heike L.; Fichtner, Iduna; Sippl, Wolfgang; Jung, Manfred

doi:10.1038/oncsis.2014.51

Cited by 101 publications

(68 citation statements)

References 61 publications

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“…Additionally, regulating acetylation levels has broader clinical relevance. Enzymes involved with acetylation are currently being targeted to treat certain cancers (146,147) and latent viral infections (148). It is possible that targeting KATs and KDACs can provide similar, yet unexplored, means to treat bacterial infections.…”

Section: Perspectivesmentioning

confidence: 99%

Regulation, Function, and Detection of Protein Acetylation in Bacteria

2017

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N -Lysine acetylation is now recognized as an abundant posttranslational modification (PTM) that influences many essential biological pathways. Advancements in mass spectrometry-based proteomics have led to the discovery that bacteria contain hundreds of acetylated proteins, contrary to the prior notion of acetylation events being rare in bacteria. Although the mechanisms that regulate protein acetylation are still not fully defined, it is understood that this modification is finely tuned via both enzymatic and nonenzymatic mechanisms. The opposing actions of Gcn5-related N-acetyltransferases (GNATs) and deacetylases, including sirtuins, provide the enzymatic control of lysine acetylation. A nonenzymatic mechanism of acetylation has also been demonstrated and proven to be prominent in bacteria, as well as in mitochondria. The functional consequences of the vast majority of the identified acetylation sites remain unknown. From studies in mammalian systems, acetylation of critical lysine residues was shown to impact protein function by altering its structure, subcellular localization, and interactions. It is becoming apparent that the same diversity of functions can be found in bacteria. Here, we review current knowledge of the mechanisms and the functional consequences of acetylation in bacteria. Additionally, we discuss the methods available for detecting acetylation sites, including quantitative mass spectrometry-based methods, which promise to promote this field of research. We conclude with possible future directions and broader implications of the study of protein acetylation in bacteria.

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Section: Perspectivesmentioning

confidence: 99%

Regulation, Function, and Detection of Protein Acetylation in Bacteria

2017

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“…19 Inhibitors of p300/CBP HAT activity have been developed and are under investigation as therapeutics for a number of diseases. 5,10,14,22,23 Additional key p300/CBP domains include a well-characterized bromodomain that is just N-terminal to the HAT domain and can bind acetyl-Lys-containing peptides. The bromodomain is one of the most highly conserved domains in p300 and CBP, possessing 96% sequence identity.…”

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confidence: 99%

Modulation of p300/CBP Acetylation of Nucleosomes by Bromodomain Ligand I-CBP112

Zucconi

Luef

et al. 2016

Biochemistry

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The histone acetyltransferase (HAT) enzymes p300 and CBP are closely related paralogs that serve as transcriptional coactivators and have been found to be dysregulated in cancer and other diseases. p300/CBP is a multidomain protein and possesses a highly conserved bromodomain that has been shown to bind acetylated Lys residues in both proteins and various small molecules, including I-CBP112 and CBP30. Here we show that the ligand I-CBP112 can stimulate nucleosome acetylation up to 3-fold while CBP30 does not. Activation of p300/CBP by I-CBP112 is not observed with the isolated histone H3 substrate but requires a nucleosome substrate. I-CBP112 does not impact nucleosome acetylation by the isolated p300 HAT domain, and the effects of I-CBP112 on p300/CBP can be neutralized by CBP30, suggesting that I-CBP112 likely allosterically activates p300/CBP through bromodomain interactions. Using mass spectrometry and Western blots, we have found that I-CBP112 particularly stimulates acetylation of Lys18 of histone H3 (H3K18) in nucleosomes, an established in vivo site of p300/CBP. In addition, we show that I-CBP112 enhances H3K18 acetylation in acute leukemia and prostate cancer cells in a concentration range commensurate with its antiproliferative effects. Our findings extend the known pharmacology of bromodomain ligands in the regulation of p300/CBP and suggest a novel approach to modulating histone acetylation in cancer.

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“…Most previous studies about the roles and the related molecular mechanisms of CBP participated in carcinogenesis and development focused on its gene mutation or chromosome translocation (Lin et al, 2014;Mullighan et al, 2011;Pasqualucci et al, 2011). Only rare researches recently revealed the anti-tumor effects of CBP inhibition by suppressing its HAT activity or function as transcriptional co-activator (Arensman et al, 2014;Gajer et al, 2015;Giotopoulos et al, 2015). Nevertheless, the accurate functions and molecular mechanisms by which CBP was involved in tumor progression have still been largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Together with p300, gene mutation or chromosomal translocation within CBP gene or its aberrant recruitment at chromatin structure has been identified to be associated with several types of cancer, including tumors arising from colon and rectum, stomach, breast, pancreas cancers, ovarian and acute myeloid leukemia (Mullighan et al., 2011; Pasqualucci et al., 2011). Moreover, the inhibition of histone acetyltransferase activity of CBP/p300 or the inhibition of CBP's activity as transcriptional co‐activator have been found to be able to block cancer cell growth in vitro and in vivo in neuroblastoma, pancreatic cancer, acute myeloid leukemia (Arensman et al., 2014; Gajer et al., 2015; Giotopoulos et al., 2015). In lung cancer, the patients with CBP‐positive expression had shown significantly lower OS (Overall Survival) and DFS (Disease Free Survival) than those with CBP‐negative tumors (Gao et al., 2014).…”

Section: Introductionmentioning

confidence: 99%