Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Richters, André; Koehler, Angela N.

doi:10.2174/0929867324666170223153115

Cited by 26 publications

(22 citation statements)

References 163 publications

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“…Both enzymes have an ~160-residue HAT domain and a C-terminal bromodomain and have a strong preference, among histones, for acetylation of H3K14 [38]. Both HATs are ubiquitously expressed, with GCN5 functioning as part of the SAGA and ATAC complexes [38,39], whereas PCAF can be autoacetylated or acetylated by p300, and both HATs can acetylate a variety of non-histone, as well as histone, proteins [40]. Gcn5-deleted mice die during embryogenesis, with failure to develop dorsal mesodermal structures, including the neural tube [18,19].…”

Section: Discussionmentioning

confidence: 99%

Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Liu

Bao

Wang

et al. 2019

Cancers

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Functions of the GCN5-related N-acetyltransferase (GNAT) family of histone/protein acetyltransferases (HATs) in Foxp3+ T-regulatory (Treg) cells are unexplored, despite the general importance of these enzymes in cell biology. We now show that two prototypical GNAT family members, GCN5 (general control nonrepressed-protein 5, lysine acetyltransferase (KAT)2a) and p300/CBP-associated factor (p300/CBP-associated factor (PCAF), Kat2b) contribute to Treg functions through partially distinct and partially overlapping mechanisms. Deletion of Gcn5 or PCAF did not affect Treg development or suppressive function in vitro, but did affect inducible Treg (iTreg) development, and in vivo, abrogated Treg-dependent allograft survival. Contrasting effects were seen upon targeting of each HAT in all T cells; mice lacking GCN5 showed prolonged allograft survival, suggesting this HAT might be a target for epigenetic therapy in allograft recipients, whereas transplants in mice lacking PCAF underwent acute allograft rejection. PCAF deletion also enhanced anti-tumor immunity in immunocompetent mice. Dual deletion of GCN5 and PCAF led to decreased Treg stability and numbers in peripheral lymphoid tissues, and mice succumbed to severe autoimmunity by 3–4 weeks of life. These data indicate that HATs of the GNAT family have contributions to Treg function that cannot be replaced by the functions of previously characterized Treg HATs (CBP, p300, and Tip60), and may be useful targets in immuno-oncology.

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Section: Discussionmentioning

confidence: 99%

Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Liu

Bao

Wang

et al. 2019

Cancers

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“…Inhibitors targeting HATs are considered as potential drugs for cancer therapy [ 34 , 35 ]. Typically, these compounds inhibit two or more paralogous enzymes like CBP/p300 or PCAF/GCN5 [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Histone Acetyltransferase GCN5 or PCAF Knockdown on Urothelial Carcinoma Cells

Koutsogiannouli

Wagner

Hader

et al. 2017

IJMS

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Disturbances in histone acetyltransferases (HATs) are common in cancers. In urothelial carcinoma (UC), p300 and CBP are often mutated, whereas the GNAT family HATs GCN5 and PCAF (General Control Nonderepressible 5, p300/CBP-Associated Factor) are often upregulated. Here, we explored the effects of specific siRNA-mediated knockdown of GCN5, PCAF or both in four UC cell lines (UCCs). Expression of various HATs and marker proteins was measured by qRT-PCR and western blot. Cellular effects of knockdowns were analyzed by flow cytometry and ATP-, caspase-, and colony forming-assays. GCN5 was regularly upregulated in UCCs, whereas PCAF was variable. Knockdown of GCN5 or both GNATs, but not of PCAF alone, diminished viability and inhibited clonogenic growth in 2/4 UCCs, inducing cell cycle changes and caspase-3/7 activity. PCAF knockdown elicited GCN5 mRNA upregulation. Double knockdown increased c-MYC and MDM2 (Mouse Double Minute 2) in most cell lines. In conclusion, GCN5 upregulation is especially common in UCCs. GCN5 knockdown impeded growth of specific UCCs, whereas PCAF knockdown elicited minor effects. The limited sensitivity towards GNAT knockdown and its variation between the cell lines might be due to compensatory effects including HAT, c-MYC and MDM2 upregulation. Our results predict that developing drugs targeting individual HATs for UC treatment may be challenging.

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“…The proteins of the histone acetylation cycle have clinical significance in cancer (Somech et al, 2004;Jain and Barton, 2017;Richters and Koehler, 2017) and have attracted interest as potential druggable targets. For example, translocation of BRD-containing BRD4 to NUTM1 in human cells generates an oncoprotein that drives a rare and aggressive form of squamous cell carcinoma, NUT midline carcinoma (NMC) (French et al, 2004).…”

Section: The Histone Acetylation Cycle and Its Relevance To Human Dismentioning

confidence: 99%

Exploring the Histone Acetylation Cycle in the Protozoan Model Tetrahymena thermophila

Wahab

Saettone

Nabeel‐Shah

et al. 2020

Front. Cell Dev. Biol.

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The eukaryotic histone acetylation cycle is composed of three classes of proteins, histone acetyltransferases (HATs) that add acetyl groups to lysine amino acids, bromodomain (BRD) containing proteins that are one of the most characterized of several protein domains that recognize acetyl-lysine (Kac) and effect downstream function, and histone deacetylases (HDACs) that catalyze the reverse reaction. Dysfunction of selected proteins of these three classes is associated with human disease such as cancer. Additionally, the HATs, BRDs, and HDACs of fungi and parasitic protozoa present potential drug targets. Despite their importance, the function and mechanisms of HATs, BRDs, and HDACs and how they relate to chromatin remodeling (CR) remain incompletely understood. Tetrahymena thermophila (Tt) provides a highly tractable single-celled free-living protozoan model for studying histone acetylation, featuring a massively acetylated somatic genome, a property that was exploited in the identification of the first nuclear/type A HAT Gcn5 in the 1990s. Since then, Tetrahymena remains an under-explored model for the molecular analysis of HATs, BRDs, and HDACs. Studies of HATs, BRDs, and HDACs in Tetrahymena have the potential to reveal the function of HATs and BRDs relevant to both fundamental eukaryotic biology and to the study of disease mechanisms in parasitic protozoa.

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Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Cited by 26 publications

References 163 publications

Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Complementary Roles of GCN5 and PCAF in Foxp3+ T-Regulatory Cells

Differential Effects of Histone Acetyltransferase GCN5 or PCAF Knockdown on Urothelial Carcinoma Cells

Exploring the Histone Acetylation Cycle in the Protozoan Model Tetrahymena thermophila

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