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Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor
Open accessAbstract
Histone deacetylases (HDACs) are a family of enzymes involved in the regulation of gene expression, DNA repair, and stress response. These processes often are altered in tumors, and HDAC inhibitors have had pronounced antitumor activity with promising results in clinical trials. Here, we report the crystal structure of human HDAC8 in complex with a hydroxamic acid inhibitor. Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously. Similar to bacterial HDAC-like protein, HDAC8 folds in a single α/β domain. The inhibitor and the zinc-binding sites are similar in both proteins. However, significant differences are observed in the length and structure of the loops surrounding the active site, including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues. CD data suggest a direct role of potassium in the fold stabilization of HDAC8. Knockdown of HDAC8 by RNA interference inhibits growth of human lung, colon, and cervical cancer cell lines, highlighting the importance of this HDAC subtype for tumor cell proliferation. Our findings open the way for the design and development of selective inhibitors of HDAC8 as possible antitumor agents.
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TL;DR
The paper reports the crystal structure of human HDAC8, a eukaryotic zinc-dependent histone deacetylase, in complex with a hydroxamic acid inhibitor, revealing a single α/β domain, a pentacoordinated active-site Zn²⁺, and two bound K⁺ ions. It also shows that HDAC8 has a distinct inhibitor profile and that siRNA knockdown of HDAC8 inhibits proliferation of A549, HeLa, and HCT116 tumor cell lines.
Key findings
- The HDAC8 monomer folds as a single compact α/β domain with a central eight-stranded parallel β-sheet and 11 α-helices; the crystal contains a head-to-head dimer burying ≈1,300 Ų, but size-exclusion chromatography and light scattering are compatible with a monomer in solution. The active-site Zn²⁺ is pentacoordinated by Asp-178, His-180, Asp-267, and the hydroxamate inhibitor.
- Two K⁺ sites were identified: site 1 is 7.0 Å from the zinc site and site 2 is 15 Å from site 1, with peaks of 19σ and 13σ, respectively. K⁺ site 1 contacts backbone carbonyls of Asp-178 and His-180, whose side chains coordinate zinc. CD spectroscopy showed a melting midpoint of ≈35.5°C in NaCl versus ≈41°C in KCl.
- HDAC8 inhibition differed from HDAC1 and HDAC3: IC₅₀ values for HDAC8/HDAC1/HDAC3 were TSA 490/1.5/0.6 nM, SAHA 4,000/119/106 nM, Compound 1 175.5/86.0/44 nM, MS27-275 >10,000/185/201 nM, and apicidin >1,000/2/0.7 nM. Compound 1 showed relatively similar potency across all three enzymes (<4-fold differences).
- Two HDAC8 siRNAs inhibited proliferation in A549, HeLa, and HCT116 cells; an Eg5 siRNA gave comparable growth inhibition, whereas an unrelated Luc siRNA had no effect.
Methods
- Human HDAC8 was expressed and purified, then crystallized after incubation of 130 μM HDAC8 with a 6.7 molar excess of inhibitor for 1 h at room temperature. Crystals were grown by sitting-drop vapor diffusion; data were collected at 100 K using synchrotron radiation.
- The structure was solved by molecular replacement using a truncated homology model of HDAC8 residues 63–320 based on the HDLP–TSA structure (PDB 1C3R), and refined to 2.5 Å with final R and R_free of 0.21 and 0.25.
- CD spectroscopy measured thermal unfolding in KCl- or NaCl-containing buffers. siRNA transfection and cell-growth assays were performed in A549, HeLa, and HCT116 cells; HDAC inhibition assays tested HDAC1, HDAC3, and HDAC8 against a panel of inhibitors.
Limitations
- The paper states no formal limitations section. It notes that the crystal dimer is mediated by the inhibitor and is unlikely to occur in solution, and that the relevance of potassium-binding site 2 for catalytic activity is not obvious from the structure.
- Evident from the text: the structural conclusions come from one 2.5-Å crystal form; potassium-binding site 1 was identified at 75 mM K⁺ in the crystallization drop, lower than the intracellular physiological value of ≈150 mM; and the RNAi proliferation data are limited to three human tumor cell lines with no in vivo results.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Potassium-binding site 2 ([Fig. 6*B*](#fig6)) is formed by the main-chain carbonyl oxygen of residues Phe-189, Thr-192, Val-195, and Tyr-225 and two water molecules.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Compound 1, an aryl hydroxamic acid identified by screening a collection of small molecules, instead showed relatively similar potencies (<4-fold differences) on all tested proteins.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“In the active site, the van der Waals surface of the enzyme reveals an ≈12-Å-deep, narrow pocket likely to accommodate the acetylated lysine during the catalytic reaction.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Potassium-binding site 1 is directly connected with the zinc-binding site, because the K+ ion is coordinated by the main-chain carbonyl oxygens of Asp-178 and His-180, whose side chains are involved in zinc chelation ([Fig. 4*A*](#fig4)).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“each capping group interacts with protein residues Pro-273 and Tyr-306 of the opposite molecule, forming an extensive hydrophobic sandwich”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Additional van der Waals interactions occur between the linker region and the side chain of Met-274 and the main chain of Gly-151.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“At site 1, the K+ ion is hexacoordinated by six oxygen ligands from Asp-176 (main-chain carbonyl oxygen and Oδ1), Asp-178 (main-chain carbonyl oxygen), His-180 (main-chain carbonyl oxygen), Ser-199 (Oγ), and Leu-200 (main-chain carbonyl oxygen), arranged in a distorted octahedral geometry ([Fig. 6*B*](#fig6)).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The two molecules are essentially identical (rms deviation 0.34 Å for the Cα trace)”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The twisted β-sheet (topology β2, -1, -3, -8, -7, -4, -5, and -6) is flanked by five helices on one side (topology α2, -10, -9, -8, and -11) and three helices (topology α5, -6, and -7) on the other.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Thus, HDAC8 shows a more restricted inhibition pattern than other class I enzymes”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Residues at potassium-binding site 1 are conserved in all zinc-dependent HDACs, with the exception of Leu-200, which can be substituted with Phe (HDAC1, -2, and -3) or Trp (HDAC10).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Each molecule binds one Zn2+ ion and two K+ ions.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“the loop region featuring the equivalent of Pro-22 from HDLP (Ala-32 in HDAC8), a residue that interacts with the capping group of TSA inhibitor ([11](#ref11)), is shorter in HDAC8, and therefore this interaction is not possible ([Fig. 2*C*](#fig2))”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
What the sources say
- Not checked yetcites [11] Finnin, M. S., Donigian, J. R., Cohen, A., Richon, V. M., Rifkind, R. A., Marks, P. A., Breslow, R. & Pavletich, N. P. (1999) Nature 401**,** 188–193. [[DOI](https://doi.org/10.1038/43710)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/10490031/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nature&volume=401&publication_year=1999&pages=188&pmid=10490031&doi=10.1038/43710&)] source
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In the paper
“Similar to bacterial HDAC-like protein, HDAC8 folds in a single α/β domain.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Abstract
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In the paper
“All residues contacting the linker are conserved except for Met-274, which is a Leu in all other class I and II HDACs with the exception of HDAC10, which has a Glu in this position.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“including the presence of two potassium ions in HDAC8 structure, one of which interacts with key catalytic residues.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Abstract
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In the paper
“Most strikingly, the loop 332–345, part of the long extended linker between α10 and -11, is 10 residues shorter than that observed in HDLP, leaving the active site less shielded from one side”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The two potassium-binding sites are placed on the same face of the β-sheet and contribute equally to anchoring helix α7 and its loops to the central β-sheet ([Fig. 6*B*](#fig6)).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The cyclic linker region of the inhibitor fits in the hydrophobic channel, with its aromatic aryl moiety stacked between side chains of Phe-152 and -208.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“TSA and SAHA, both poor HDAC8 inhibitors ([Table 1](#tbl1))”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Unexpectedly, the structure of HDAC8 reveals K+ ions bound at two sites: Site 1 is in close proximity (7.0 Å) to the zinc-binding site, whereas site 2 is located more toward the periphery of the molecule, 15 Å away from site 1 ([Fig. 6*B*](#fig6)).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Residues forming the two potassium-binding sites come from loops contiguous to helix α7 (Asp-178 and His-180 at site 1; Phe-189 and Thr-192 at site 2) and from strands β4, -5, and -6 (Asp-176, Ser-199, and Leu-200 at site 1; Val-195 and Tyr-225 at site 2).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The authors describe the structure of human HDAC8 with four inhibitors. Their structures are comparable to ours.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Acknowledgments
What the sources say
- Not checked yetcites [21] Somoza, J. R., Skene, R. J., Katz, B. A., Mol, C., Ho, J. D., Jennings, A. J., Luong, C., Arvai, A., Buggy, J. J., Chi, E., *et al.* (2004) Structure 7**,** 1325–1334. [[DOI](https://doi.org/10.1016/j.str.2004.04.012)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15242608/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Structure&volume=7&publication_year=2004&pages=1325&pmid=15242608&doi=10.1016/j.str.2004.04.012&)]
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In the paper
“the results of size-exclusion chromatography and light-scattering experiments are compatible with a monomeric state for both the apoprotein and the protein–inhibitor complex (data not shown).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The capping group of the inhibitor is oriented in the direction of pocket d, even if this moiety does not interact with the protein but points toward the solvent.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The sequence conservation at this site is somewhat lower than at site 1: Thr-192 is Asp in class II HDACs; Val-195 is different only in HDAC9 (Ile); and Tyr-225 is different only in HDAC10 (Phe).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The presence of K+ in the active site can be expected to influence the catalytic mechanism of the deacetylation reaction in several aspects.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“The exchange with Na+ ions, which share with K+ the same external electronic configuration but a remarkably smaller ionic radius, could alter the overall folding of the enzyme, in agreement with the decreased protein stability observed when the protein was purified in the presence of NaCl (data not shown).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Trp-141 is replaced by Leu in HDAC1 and -3, which should leave more space to accommodate this inhibitor and is in line with the increased potency toward HDAC1 and -3.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“By analogy to Ca2+-binding proteins ([20](#ref20)), upon chelation with the cation, the two CO bonds of the Asp-176 side chain no longer should be equivalent, with the bond of the chelating oxygen having more single-bond character and that of the nonchelating oxygen, hydrogen-bonded to His-142, more double-bond character.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
What the sources say
- Not checked yetcites [20] Mizuguchi, M., Nara, M., Kawano, K. & Nitta, K. (1997) FEBS Lett. 417**,** 153–156. [[DOI](https://doi.org/10.1016/s0014-5793(97)01274-x)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/9395095/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=FEBS%20Lett.&volume=417&publication_year=1997&pages=153&pmid=9395095&doi=10.1016/s0014-5793(97)01274-x&)]
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In the paper
“The two sites were identified by strong positive peaks (19 and 13 σ, respectively) in the *F*o – *F*c maps and had typical distances and hexacoordination geometry for potassium binding ([19](#ref19)).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
What the sources say
- Not checked yetcites [19] Harding, M. M. (2002) Acta Crystallogr. D 58**,** 872–874. [[DOI](https://doi.org/10.1107/s0907444902003712)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/11976508/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Acta%20Crystallogr.%20D&volume=58&publication_year=2002&pages=872&pmid=11976508&doi=10.1107/s0907444902003712&)] source
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In the paper
“This finding is in line with the increased potency of TSA and SAHA observed on HDAC1 and -3 with respect to HDAC8.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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In the paper
“Data deposition: The coordinates and structure factors have been deposited in the Protein Data Bank, [www.pdb.org](http://www.pdb.org) (PDB ID code 1W22).”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Acknowledgments
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In the paper
“First, its presence increases the positive electrostatic potential in the active site and therefore could contribute to stabilize the oxyanion formed in the transition state of the deacetylation reaction and/or to stabilize the negatively charged acetate product.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The final concentration of K+ ions in the crystallization drop is 75 mM, a value lower than its intracellular physiological value of ≈150 mM, suggesting that the potassium-binding sites could be biologically relevant.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
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- Rests on an assumption: The intracellular physiological K+ concentration is approximately 150 mM.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These chains act as optimal linkers for the hydroxamic acid and the capping group, allowing contacts both at the bottom and the entrance of the pocket.”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“It is conceivable that structural variability in the loop regions emerging from the conserved core will be found across the entire family of HDACs”
§ Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor > Results and Discussion
Strength:hedged· not yet calibratedTests✗ Asserted: fails✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
The paper relies on this without support.
No structure of a eukaryotic zinc-dependent HDAC had been described before this study.
“Such a structure of a eukaryotic zinc-dependent HDAC has not be described previously.”
The paper relies on this without support.
The dimeric arrangement seen in the crystal has not been found in solution.
“given that the dimeric arrangement seen in the crystal has not been found in solution”
The paper relies on this without support.
The intracellular physiological K+ concentration is approximately 150 mM.
“a value lower than its intracellular physiological value of ≈150 mM”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Crystal structures of human HDAC8, in complex with different inhibitors, have been reported; they revealed a single α/β-domain with a core eight-stranded parallel β-sheet and 11 α-helices.7, 31, 32”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [7]
In the citing paper
“More generally, HDAC8 affects cell proliferation in different tumor types (Vannini et al., 2004).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Vannini et al., 2004
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
HDAC8 is both described as having Ala and included among enzymes with Pro at the same position
MinorThe paper identifies Ala-32 in HDAC8 as equivalent to Pro-22 in HDLP, then says that all class I and II HDACs except HDAC10 have Pro at that position. HDAC8 is identified elsewhere in the paper as a class I HDAC.
“the equivalent of Pro-22 from HDLP (Ala-32 in HDAC8)”
“A Pro is present in this position in all class I and II HDACs, with the exception of HDAC10, which has an Ile”
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Effects of trichostatin A on HDAC8 expression, proliferation and cell cycle of Molt-4 cells
He, J., Liu, H., & Chen, Y. (2006) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-006-0511-x · Cited by 7
Metadata
- Authors
- Vannini, A., Volpari, C., Filocamo, G., Casavola, E. C., Brunetti, M., Renzoni, D., Chakravarty, P., Paolini, C., De Francesco, R., Gallinari, P., Steinkühler, C., & Di Marco, S.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Department of Biochemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy; and Department of Medicinal Chemistry, Merck and Company, Inc., Rahway, NJ 07065
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-10-11
- Volume
- 101
- Issue
- 42
- Pages
- 15064-15069
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC524051
- OpenAlex
- W2078454854
- Semantic Scholar
- 03c10a313fe9a3fe15c2052dfba5f2319155ebba
- Cited by
- 638
- References
- 23
- Citations by year
- 2026: 19 · 2025: 13 · 2024: 25 · 2023: 17 · 2022: 18 · 2021: 19 · 2020: 23 · 2019: 27 · 2018: 20 · 2017: 27 · 2016: 34 · 2015: 37 · 2014: 30 · 2013: 34 · 2012: 40
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- HDAC8, histone deacetylase, hydroxamate inhibitors, zinc metalloenzyme, crystal structure, potassium ions, active site, anticancer agents, histone deacetylase inhibitors, tumor cell proliferation, RNAi knockdown
- MeSH terms
- Amino Acid Sequence, Antineoplastic Agents, Circular Dichroism, Enzyme Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Models, Molecular, Molecular Sequence Data, Potassium, Protein Conformation, Recombinant Proteins, Repressor Proteins, Zinc, Drug Design, Sequence Homology, Amino Acid, Crystallography, X-Ray, Catalytic Domain, RNA Interference, Cell Line, Tumor, Histone Deacetylase Inhibitors, In Vitro Techniques
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