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Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases
Open accessAbstract
Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nε2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this “gain of function phenotype” could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro . Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
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TL;DR
Vertebrate class IIa HDACs carry a conserved active-site Tyr-to-His substitution that makes them very inefficient on canonical acetyl-lysine substrates, with most deacetylase activity in class IIa complexes coming from associated class I HDACs. A single His-to-Tyr mutation restores high catalytic activity, and trifluoroacetyl-lysine is identified as a class IIa-specific substrate in vitro.
Key findings
- The catalytic Tyr conserved in other HDACs is replaced by His in vertebrate class IIa HDACs; mutating HDAC3 Y298 to H abolished activity on pepH4-AcK16, and HDAC1 Y303H reduced activity 5- to 8-fold.
- HDAC4 catalytic domain purified from E. coli had measurable activity but was at least 1,000-fold lower than class I HDACs and 100-fold lower than the HDAC4-FLAG complex; it was inactive on pepH4-AcK16.
- HDAC4 H976Y produced a gain-of-function phenotype: >20-fold increased activity for HDAC4-FLAG and >1,000-fold for HDAC4-CD, reaching levels comparable to class I enzymes; similar effects were seen for HDAC5 H1006Y and HDAC7 H843Y.
- Trifluoroacetyl-lysine was identified as a class IIa-specific substrate in vitro, processed by HDAC4 full-length and catalytic domain and by three class IIa enzymes, but poorly by class I and class IIb HDACs.
Methods
- HDAC4 was used as a representative class IIa model with four approaches: HDAC inhibitor binding/inhibition comparison, functional analysis of purified HDAC4 catalytic domain expressed in E. coli, structure-guided mutagenesis, and substrate screening.
- Deacetylase assays used 3[H]acetyl-core histones purified from HeLa cells or fluorescent pepH4-AcK16, plus a commercial Fluor de Lys assay; HDAC inhibitor activities were measured by preincubation with enzymes before substrate addition.
- Binding was assessed by pull-down with biotinylated LAQ824/apicidin derivatives and by UV cross-linking; sequence analysis used CLUSTALW/Genedoc and structural analysis used bacterial class II homolog PDB 1ZZ1.
Limitations
- Stated: the lack of isotype/class-specific HDAC inhibitors limits distinguishing class IIa intrinsic activity from associated class I HDACs; attempts to obtain active recombinant class IIa HDACs in heterologous systems were unsuccessful, and it remains unknown whether this reflects missing cofactors or endogenous class I enzymes.
- Stated: the precise role of HDAC4 catalytic activity in atypical biological contexts remains to be elucidated, and identification of additional biological activities/substrates dependent on class IIa H-associated activity requires further work.
- Evident from the text: the study relies heavily on in vitro assays and ectopically expressed proteins, and no natural physiological class IIa-specific substrate is identified; the proposed specialized vertebrate class IIa activity is therefore inferred from synthetic substrate data.
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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
“Finally, we have identified trif luoroacetyl-lysine as a class IIa-specific substrate in vitro.”
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In the paper
“However, the Y298H substitution in HDAC3 did not affect its association with N-CoR DAD (Fig. 2B), suggesting that the integrity of the catalytic domain was preserved.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
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In the paper
“Furthermore, replacement of Y with H produced a loss-of-function phenotype as severe as that caused by replacement with F (SI Fig. 8A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“As predicted, replacing the active site Y with H was sufficient to abolish the enzymatic activity on a histone H4-derived peptide containing a single acetyl-lysine (pepH4-AcK16) (Fig. 2A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
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In the paper
“As shown in SI Fig. 8C, the mutation actually reduced HDAC1 deacetylase activity 5-to 8-fold.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
“Class IIa HDACs possess a weak but measurable intrinsic capability of hydrolyzing acetyl-lysines in vitro.”
- Also stated in: § HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs. · plain
“HDAC4-CD showed a measurable deacetylase activity both in the histone-based (Fig. 4B) and the commercial (SI Fig. 10A) HDAC assays.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs. · plain
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
“Indeed, catalytic activity toward canonical HDAC substrates could be restored by a single H-to-Y substitution in the active site.”
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In the paper
“As shown in SI Fig. 8E, mutation into F did not alter the activity of the purified HDAC4 complex on pepH4-AcK16.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Class IIa HDACs with the H Mutated into F Are Not Impaired in Their
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In the paper
“The H976Y mutation did not enhance HDAC4 transcriptional inhibitory activity, despite its clear effect on the enzymatic activity in vitro (SI Fig. 12 A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
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In the paper
“When challenged in activity assays, HDAC4-CD showed a measurable deacetylase activity both in the histone-based (Fig. 4B) and the commercial (SI Fig. 10A) HDAC assays.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
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- It may state two separate claims as one. 23
- The quote only partly states this claim. 1
- Probably not a substantial claim. 4
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
“In the vertebrate class IIa HDACs, the catalytic Y is replaced by an H, a conservative substitution, whereas other functional residues are virtually always conserved (SI Fig. 7).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Sequence and Structure Analysis Indicates that Vertebrate Class IIa
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In the paper
“This protein was efficiently pulled-down on biotinylated LAQ824 beads (Fig. 4A), suggesting that the structural integrity of the catalytic domain was preserved in the recombinant truncated mutant.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
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In the paper
“However, LAQ824 and apicidin had similar effects in this assay in contrast to the different inhibitory potencies and binding affinities shown in vitro.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
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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
“Again Y mutants exhibited strongly increased activity compared with WT and, like the HDAC4 mutant, could be inhibited by LAQ824 but were resistant to apicidin.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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In the paper
“Pull-down was significantly reduced by preincubation with an excess of free LAQ824, whereas apicidin and MS275 did not show competition, thus confirming and directly validating the results obtained with ectopic HDAC4-FLAG.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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
“Different than WT HDAC4-FLAG, Y mutants were sensitive only to the inhibitory effect of LAQ824, but they were highly resistant to inhibition by compounds belonging to different chemical classes (MS-275, apicidin, and its open derivative), all of which are active on class I HDACs (data not shown).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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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
“In addition, HDAC4-CD was completely inactive on pepH4-AcK16 and on a number of acetylated peptides grafted from nonhistonic HDAC substrates (data not shown).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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
“Having ascertained that class IIa HDACs are not proficient enzymes on acetyl-lysines, we sought alternative in vitro substrates.”
- Also stated in: § HDAC4 Compound Binding Assays. · boosted
“Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Identification of a Class IIa-Specific Substrate.
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § HDAC4 Compound Binding Assays. · boosted
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
“Moreover, this compound was actively and specifically processed by three different class IIa enzymes, whereas it was a poor substrate for both class I and class IIb HDACs (Fig. 6).”
- Also stated in: § Discussion · plain
“We have identified a class IIa-specific synthetic substrate, trifluoroacetyl-lysine.”
- Also stated in: § HDAC4 Compound Binding Assays. · plain
“Trifluoroacetyl-lysine is a class IIa-specific substrate in vitro.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Identification of a Class IIa-Specific Substrate.
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- Also stated in: § Discussion · plain
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
“We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Compound Binding Assays.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
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In the paper
“Interestingly, ascidian class IIa sequences also lack one of the conserved Zn ligands, a D is replaced by an S (SI Fig. 7).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Strength:plain· 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
“In class IIa HDACs, three different residues (Y, H, and F) are observed at this position and, given the particular structural context, it is unlikely that for each residue a concomitant conformational change would occur.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Sequence and Structure Analysis Indicates that Vertebrate Class IIa
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In the paper
“This experimental evidence also proved the HDAC4 catalytic domain to be properly folded under our experimental conditions, because a single amino acid substitution was sufficient to confer high enzymatic activity.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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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
“Furthermore, the HDAC4-CD mutant showed an inhibition profile identical to that of the full-length HDAC4-FLAG mutant, suggesting that the observed selectivity is directly related to the catalytic domain and does not depend on additional N-terminal regions.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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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
“Together, these results demonstrate that HDAC4 intrinsic catalytic activity is low on canonical acetylated substrates and does not contribute significantly to the overall activity observed in purified ectopic HDAC4 complexes.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“All class IIa members expressed in mammalian cells are known to recruit class I HDACs, which possess high deacetylase activities both in vitro and in cells (18)(19)(20).”
What the sources say
- Not checked yetcites (18)(19)(20)
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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
“Remarkably, compounds that did not inhibit the H976Ysubstituted enzymes were those that did not bind WT HDAC4, thus implying that the mutant proteins retain the WT selectivity of interactions.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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In the paper
“It is well documented that class IIa HDACs are potent and selective transcriptional repressors (4).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
What the sources say
- Not checked yetcites [4] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding was confirmed both in the isolated catalytic domain expressed in a prokaryotic system as well as for the full-length enzymes expressed in mammalian cells, including HDAC5 and -7.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > 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 emergent theme predicts class IIa HDACs with intrinsically different catalytic activities for the two groups: (i) canonical HDAC activity in invertebrates and (ii) a more specialized enzymatic activity in vertebrates.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
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
“Mechanistically, the presence of the trifluoro group should destabilize the amide bond and thus favor the reaction even in the absence of transition-state stabilization, as postulated for the His-containing class IIa HDACs.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean values of at least two independent assays are reported.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Methods Sequence Analysis and Modeling.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Our MEF2 reporter gene data are in agreement with these findings, excluding HDAC4 catalytic activity for being responsible for transcriptional repression and pointing to the involvement of class I enzymes that are equally sensitive to the inhibition by both LAQ824 and apicidin.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ 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
“Finally, our data also imply that class IIa HDACs should be considered a distinct class of therapeutic targets, concerning both their natural substrates and selective mechanisms of inhibition.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: Vertebrate class IIa HDACs have natural substrates that are not canonical acetyl-lysines.
- Rests on an assumption: In vitro substrate specificity of class IIa HDACs reflects their in vivo biological function.
None of the sources cited for this claim have been checked yet.
In the paper
“More recently, it has been shown that both Sirt1 (28) and HDAC3 (29), and not HDAC4 or -5, efficiently deacetylate MEF2D, thus contributing to MEF2Ddependent transcriptional repression.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The authors state this as an assumption.
The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
“Based on our results, the presence of an F should be incompatible with activity, provided that the catalytic mechanism is conserved.”
The paper relies on this without support.
Vertebrate class IIa HDACs have natural substrates that are not canonical acetyl-lysines.
“Future work will undoubtedly identify these yet unknown physiological substrates and further reveal the already complex biological activities of these enzymes.”
The paper relies on this without support.
In vitro substrate specificity of class IIa HDACs reflects their in vivo biological function.
“our results point to a previously unknown, specific catalytic activity of vertebrate class IIa HDACs.”
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
“Class IIa enzymes (Lahm et al., 2007) as well as HDAC3 (Madsen and Olsen, 2012a), HDAC8 (Bradner et al., 2010), and HDAC11 (Inks et al., 2012) removed the physiologically non-relevant trifluoroacetamide (Ktfa).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Lahm et al., 2007
In the citing paper
“In vertebrates, this subfamily is characterized by limited catalytic activity, mainly due to the replacement of a tyrosine (Y) with a histidine (H) residue in the enzymatic pocket (Lahm et al., 2007).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Lahm et al., 2007
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.
Claim of universal Tyr conservation overlooks ascidian class IIa homologs
MinorThe first statement says Tyr is conserved in every HDAC outside vertebrate class IIa enzymes. The paper later identifies ascidian class IIa homologs with Phe at that position; ascidians are not vertebrates.
“A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His.”
“Yet another residue, F, is instead found in class IIa homologs of the ascidians Ciona intestinalis, Ciona savignyi, and Halocynthia roretzi.”
Citations
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Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy
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Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis
Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., et al. (2004) · Cell · doi:10.1016/j.cell.2004.10.024 · Cited by 805
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Items 301–400 of 609
HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications
Cuttini, E., Goi, C., Pellarin, E., Vida, R., & Brancolini, C. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1116660 · Cited by 28
Guo, X. V., Wang, S.-B., Xu, H., Ribic, A., Mohns, E. J., Zhou, Y., Zhu, X., Biederer, T., Crair, M. C., & Chen, B. (2015) · Nature Communications · doi:10.1038/ncomms9005 · Cited by 28
Hutt, D. M., Olsen, C. A., Vickers, C. J., Herman, D., Chalfant, M. A., Montero, A., Leman, L. J., Burkle, R., Maryanoff, B. E., Balch, W. E., et al. (2011) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200136e · Cited by 28
Discovery and Mechanism of Natural Products as Modulators of Histone Acetylation
Salvador, L. A., & Luesch, H. (2012) · Current Drug Targets · doi:10.2174/138945012802008973 · Cited by 29
Butler, K. V., Chiarella, A. M., Jin, J. J., & Hathaway, N. A. (2017) · ACS Synthetic Biology · doi:10.1021/acssynbio.7b00295 · Cited by 31
Regulation of Central Nervous System Development by Class I Histone Deacetylases
D’Mello, S. R. (2019) · Developmental Neuroscience · doi:10.1159/000505535 · Cited by 28
Reversible histone deacetylase activity catalyzes lysine acylation
Tsusaka, T., Najar, M. A., Schwarz, B. H., Bohrnsen, E., Osés-Prieto, J. A., Neudorf, H., Lee, C., Little, J. P., Burlingame, A. L., Bosio, C. M., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01869-5 · Cited by 29
Stratton, M. S., & McKinsey, T. A. (2014) · Biochemistry and Cell Biology · doi:10.1139/bcb-2014-0119 · Cited by 31
Tavares, M. T., Shen, S., Knox, T. J., Hadley, M. M., Kutil, Z., Bařinka, C., Villagra, A., & Kozikowski, A. P. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00223 · Cited by 28
Cho, H. M., Seok, Y. M., Lee, H. A., Song, M., & Kim, I. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113539 · Cited by 25
Role of Histone Acetylation and Acetyltransferases in Gene Regulation
Lee, C. Y., & Grant, P. A. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-812433-8.00001-0 · Cited by 32
Histone deacetylases 1, 2 and 3 in nervous system development
D’Mello, S. R. (2020) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2019.11.007 · Cited by 27
Post-translational lysine ac(et)ylation in health, ageing and disease
Blasl, A., Schulze, S., Qin, C., Graf, L. G., Vogt, R., & Lammers, M. (2021) · Biological Chemistry · doi:10.1515/hsz-2021-0139 · Cited by 30
Terracciano, S., Micco, S. D., Bifulco, G., Gallinari, P., Riccio, R., & Bruno, I. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.03.022 · Cited by 27
Self-citationBello, E. D., Noce, B., Fioravanti, R., Zwergel, C., Valente, S., Rotili, D., Fianco, G., Trisciuoglio, D., Mourão, M. D. M., Sales, P. A., et al. (2022) · ACS Infectious Diseases · doi:10.1021/acsinfecdis.2c00232 · Cited by 27
Combining HDAC inhibitors with oncolytic virotherapy for cancer therapy
Chiocca, E. A., Nakashima, H., & Nguyen, T. (2015) · Oncolytic Virotherapy · doi:10.2147/ov.s66081 · Cited by 28
Essential oil of the Persian sage, Salvia rhytidea Benth.
Sajjadi, S. E., & Ghannadi, A. (2005) · PubMed · Cited by 26
Total Synthesis of Trapoxin A, a Fungal HDAC Inhibitor from Helicoma ambiens
Servatius, P., & Kazmaier, U. (2018) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.8b01569 · Cited by 25
Kozlov, M. V., Konduktorov, K. A., Shcherbakova, A. S., & Kochetkov, S. N. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.06.006 · Cited by 26
Zhou, W., Yang, J., Saren, G., Zhao, H., Cao, K., Fu, S., Pan, X., Zhang, H., Wang, A., & Chen, X. (2020) · Theranostics · doi:10.7150/thno.44961 · Cited by 26
PROTAC chemical probes for histone deacetylase enzymes
Patel, U., Smalley, J. P., & Hodgkinson, J. T. (2023) · RSC Chemical Biology · doi:10.1039/d3cb00105a · Cited by 25
Escobar, J., Pereda, J., Arduini, A., Sandoval, J., Sabater, L., Aparisi, L., Vento, M., López‐Rodas, G., & Sastre, J. (2010) · Inflammation & Allergy - Drug Targets · doi:10.2174/187152810791292773 · Cited by 25
Evidence for a non-canonical role of HDAC5 in regulation of the cardiac Ncx1 and Bnp genes
Harris, L. G., Wang, S. H., Mani, S. K., Kasiganesan, H., Chou, C. J., & Menick, D. R. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1496 · Cited by 26
Jong, K. A. D., Barrand, S., Wood‐Bradley, R. J., Almeida, D. L., Czeczor, J. K., Lopaschuk, G. D., Armitage, J. A., & McGee, S. L. (2018) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2018.02.019 · Cited by 26
Paluvai, H., Giorgio, E. D., & Brancolini, C. (2018) · Molecular Oncology · doi:10.1002/1878-0261.12392 · Cited by 25
Scarpelli, R., Marco, A. D., Ferrigno, F., Laufer, R., Marcucci, I., Muraglia, E., Ontoria, J. M., Rowley, M., Serafini, S., Steinkühler, C., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.10.041 · Cited by 25
Self-citationKovács‐Kása, A., Kovács, L., Cherian‐Shaw, M., Patel, V. S., Meadows, M. L., Fulton, D. J., Su, Y., & Verin, A. D. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.30053 · Cited by 25
Luckhurst, C. A., Maillard, M. C., & Dominguez, C. (2018) · Worldwide Protein Data Bank · doi:10.2210/pdb6fyz/pdb · Cited by 24
Hagelkrüys, A., Mattes, K., Moos, V., Rennmayr, M., Ringbauer, M., Sawicka, A., & Seiser, C. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00639-15 · Cited by 23
Histone Acetylation and Deacetylation
Fass, D. M., Kemp, M. M., Schroeder, F. A., Wagner, F. F., Wang, Q., & Holson, E. B. (2012) · Wiley-VCH eBooks · doi:10.1002/3527600906.mcb.201100036 · Cited by 23
Synthesis of 2-(1 H -Indol-2-yl)acetamides via Brønsted Acid-Assisted Cyclization Cascade
Aksenov, N. A., Аксенов, Д. А., Skomorokhov, A. A., Prityko, L. A., Aksenov, A. V., Грязнов, Г. Д., & Rubin, M. (2020) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.0c01344 · Cited by 22
Evidence that HDAC7 acts as an epigenetic “reader” of AR acetylation through NCoR-HDAC3 dissociation
Zhang, Y., Andrade, R. E., Hanna, A. A., & Pflum, M. K. H. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.05.008 · Cited by 22
Development of Substrate‐Derived Sirtuin Inhibitors with Potential Anticancer Activity
Kuhlmann, N., Chollet, C., Baldus, L., Neundorf, I., & Lammers, M. (2017) · ChemMedChem · doi:10.1002/cmdc.201700414 · Cited by 22
HDAC5 promotes osteosarcoma progression by upregulation of Twist 1 expression
Chen, J., Xia, J., Yu, Y.-L., Wang, S., Wei, Y., Chen, F.-Y., Huang, G., & Shi, J. (2013) · Tumor Biology · doi:10.1007/s13277-013-1189-x · Cited by 22
Dai, X., Lin, A., Zhuang, L.-P., Zeng, Q., Cai, L., Wei, Y., Liang, H., Gao, W., Zhang, J., & Chen, X. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01775-1 · Cited by 24
Thaler, F. (2012) · Pharmaceutical Patent Analyst · doi:10.4155/ppa.11.3 · Cited by 21
Quis Custodiet Ipsos Custodes (Who Controls the Controllers)? Two Decades of Studies on HDAC9
Brancolini, C., Giorgio, E. D., Formisano, L., & Gagliano, T. (2021) · Life · doi:10.3390/life11020090 · Cited by 21
Class I Lysine Deacetylases Facilitate Glucocorticoid-induced Transcription*
Kadiyala, V., Patrick, N. M., Mathieu, W., Jaime-Frias, R., Pookhao, N., An, L.-L., & Smith, C. L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.505115 · Cited by 24
Stolfa, D. A., Stefanachi, A., Gajer, J. M., Nebbioso, A., Altucci, L., Cellamare, S., Jung, M., & Carotti, A. (2012) · ChemMedChem · doi:10.1002/cmdc.201200193 · Cited by 20
Lernoux, M., Schnekenburger, M., Dicato, M. A., & Diederich, M. F. (2019) · Biochemical Pharmacology · doi:10.1016/j.bcp.2019.113698 · Cited by 22
Valente, S., Tardugno, M., Conte, M., Cirilli, R., Perrone, A., Ragno, R., Simeoni, S., Tramontano, A. L., Massa, S., Nebbioso, A., et al. (2011) · ChemMedChem · doi:10.1002/cmdc.201000535 · Cited by 21
Epi-drugs as triple-negative breast cancer treatment
Idrissou, M., Sánchez, A., Penault-Llorca, F. M., Bignon, Y., & Bernard-Gallon, D. J. (2020) · Epigenomics · doi:10.2217/epi-2019-0312 · Cited by 22
Zwergel, C., Bello, E. D., Fioravanti, R., Conte, M., Nebbioso, A., Mazzone, R., Brosch, G., Mercurio, C., Varasi, M., Altucci, L., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.202000854 · Cited by 21
Ramnath, D., Gupta, K. D., Wang, Y., Abrol, R., Curson, J. E. B., Lim, J., Reid, R. C., Mansell, A., Blumenthal, A., Karunakaran, D., et al. (2021) · Journal of Leukocyte Biology · doi:10.1002/jlb.2mr1021-260r · Cited by 20
Bello, E. D., Sian, V., Bontempi, G., Zwergel, C., Fioravanti, R., Noce, B., Castiello, C., Tomassi, S., Corinti, D., Passeri, D., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.115022 · Cited by 20
New Insights into the Role of Histone Deacetylases as Coactivators of Inflammatory Gene Expression
Schmitz, M. L., & de la Vega, L. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5750 · Cited by 20
Madsen, A. S., & Olsen, C. A. (2012) · Angewandte Chemie · doi:10.1002/ange.201203754 · Cited by 20
Cytoplasmic HDAC4 recovers synaptic function in the 3×Tg mouse model of Alzheimer's disease
Colussi, C., Aceto, G., Ripoli, C., Bertozzi, A., Puma, D. D. L., Paccosi, E., D’Ascenzo, M., & Grassi, C. (2022) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12861 · Cited by 19
Koyuncuoğlu, T., Türkyılmaz, M., Gören, B., Çetınkaya, M., Cansev, M., & ALKAN, T. (2015) · Restorative Neurology and Neuroscience · doi:10.3233/rnn-150549 · Cited by 19
Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice
Gaur, V., Connor, T., Venardos, K. M., Henstridge, D. C., Martin, S. D., Swinton, C., Morrison, S., Aston‐Mourney, K., Gehrig, S. M., van Ewijk, R., et al. (2017) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12896 · Cited by 18
Structural Characterization of the SMRT Corepressor Interacting with Histone Deacetylase 7
Desravines, D. C., Martin, I. S., Schneider, R., Mas, P. J., Aleksandrova, N., Jensen, M. R., Blackledge, M. J., & Hart, D. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-03718-5 · Cited by 19
Valente, S., Trisciuoglio, D., Tardugno, M., Benedetti, R., Labella, D., Secci, D., Mercurio, C., Boggio, R., Tomassi, S., Maro, S. D., et al. (2013) · ChemMedChem · doi:10.1002/cmdc.201300005 · Cited by 19
Damme, M. V., Crompot, E., Meuleman, N., Mineur, P., Dessars, B., Housni, H. E., Bron, D., Lagneaux, L., & Stamatopoulos, B. (2014) · Epigenetics · doi:10.4161/15592294.2014.969628 · Cited by 17
Slow-Binding and Covalent HDAC Inhibition: A New Paradigm?
Raouf, Y. S., & Moreno–Yruela, C. (2024) · JACS Au · doi:10.1021/jacsau.4c00828 · Cited by 19
Finke, D., Schanze, L. M., Schreiter, F. C., Kreußer, M. M., Katus, H. A., Backs, J., & Lehmann, L. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.09.001 · Cited by 18
The Role of Histone Deacetylases in Acute Lung Injury—Friend or Foe
Luo, G., Liu, B., Fu, T., Liu, Y., Li, B., Li, N., & Geng, Q. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24097876 · Cited by 18
Zeng, Y., Bai, X., Zhu, G., Zhu, M., Peng, W., Song, J., Cai, H., Ye, L., Chen, C., Song, Y., et al. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.135093 · Cited by 18
Vorinostat-Like Molecules as Structural, Stereochemical, and Pharmacological Tools
Hanessian, S., Auzzas, L., Larsson, A., Zhang, J., Giannini, G., Gallo, G., Ciacci, A., & Cabri, W. (2010) · ACS Medicinal Chemistry Letters · doi:10.1021/ml100028g · Cited by 18
Histone deacetylase 4 (HDAC4): a new player in anorexia nervosa?
Sild, M., & Booij, L. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0366-8 · Cited by 19
Nazri, J. M., Οικονομοπούλου, Κ., de Araujo, E. D., Kraskouskaya, D., Gunning, P. T., & Chandran, V. (2023) · Critical Reviews in Clinical Laboratory Sciences · doi:10.1080/10408363.2023.2177251 · Cited by 17
Role of histone deacetylases in bone development and skeletal disorders
Wang, J. S., Yoon, S.-H., & Wein, M. N. (2020) · Bone · doi:10.1016/j.bone.2020.115606 · Cited by 19
Screening and profiling assays for HDACs and sirtuins
Howitz, K. T. (2015) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2015.10.008 · Cited by 17
Histone Deacetylase Activity Assay
Yuan, Z., Rezai‐Zadeh, N., Zhang, X. M., & Seto, E. (2009) · Methods in molecular biology · doi:10.1007/978-1-59745-190-1_19 · Cited by 17
Zhou, J., Xie, H., Liu, Z., Luo, H., & Wu, R. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500513n · Cited by 16
Nuclear-cytoplasmic shuttling of class IIa histone deacetylases regulates somatic cell reprogramming
Luo, Z., Qing, X., Benda, C., Huang, Z., Zhang, M., Huang, Y., Zhang, H., Wang, L., Lai, Y., Ward, C., et al. (2019) · Cell Regeneration · doi:10.1016/j.cr.2018.11.001 · Cited by 16
Inhibition mechanism of SAHA in HDAC: a revisit
Zhou, J., Wu, R., & Luo, H. (2015) · Physical Chemistry Chemical Physics · doi:10.1039/c5cp05633k · Cited by 16
When Food Meets Man: the Contribution of Epigenetics to Health
Fabiani, E. D., Mitro, N., Gilardi, F., Galmozzi, A., Caruso, D., & Crestani, M. (2010) · Nutrients · doi:10.3390/nu2050551 · Cited by 15
Efficient Search of Chemical Space: Navigating from Fragments to Structurally Diverse Chemotypes
Wassermann, A. M., Kutchukian, P. S., Lounkine, E., Luethi, T., Hamon, J., Bocker, M. T., Malik, H. A., Cowan‐Jacob, S. W., & Glick, M. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401309q · Cited by 16
Taha, T. Y., Anirudhan, V., Limothai, U., Loeb, D. D., Petukhov, P. A., & McLachlan, A. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008802 · Cited by 16
McMorrow, L. A., Kosalko, A., Robinson, D., Saiani, A., & Reid, A. J. (2022) · Biomolecules · doi:10.3390/biom12081128 · Cited by 15
Zinc-Dependent Histone Deacetylases in Lung Endothelial Pathobiology
Patil, R. S., Maloney, M. E., Lucas, R., Fulton, D. J., Patel, V. S., Bagi, Z. A., Kovács‐Kása, A., Kovács, L., Su, Y., & Verin, A. D. (2024) · Biomolecules · doi:10.3390/biom14020140 · Cited by 15
Dai, S., Guo, L., Dey, R., Guo, M., Zhang, X., Bates, D. L., Cayford, J., Jiang, L., Wei, H., Chen, Z., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae036 · Cited by 14
HDAC7: a promising target in cancer
Liu, C., Zheng, D., Pu, X., & Li, S. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1327933 · Cited by 18
Rationale for HDAC Inhibitor Therapy in Autoimmunity and Transplantation
Hancock, W. W. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-21631-2_6 · Cited by 15
Gu, X., Huang, X., Li, D., Bi, N., Yu, X., & Wang, H.-L. (2020) · NeuroToxicology · doi:10.1016/j.neuro.2020.10.006 · Cited by 15
Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells
Fukui, T., Asakura, K., Hikichi, C., Ishikawa, T., Murai, R., Hirota, S., Murate, K., Kizawa, M., Ueda, A., Ito, S., et al. (2015) · Toxicology · doi:10.1016/j.tox.2015.01.013 · Cited by 15
Novel Antiproliferative Chimeric Compounds with Marked Histone Deacetylase Inhibitory Activity
Giacomini, E., Nebbioso, A., Ciotta, A., Ianni, C., Falchi, F., Roberti, M., Tolomeo, M., Grimaudo, S., Cristina, A. D., Pipitone, R. M., et al. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml5000959 · Cited by 15
Histone acetylation modulators in breast cancer
Yuan, X., & Rosen, J. M. (2025) · Breast Cancer Research · doi:10.1186/s13058-025-02006-9 · Cited by 14
Cassandri, M., Porrazzo, A., Pomella, S., Noce, B., Zwergel, C., Aiello, F. A., Vulcano, F., Milazzo, L., Camero, S., Pajalunga, D., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02115-y · Cited by 14
Post-translational modifications talk and crosstalk to class IIa histone deacetylases
Guttzeit, S., & Backs, J. (2021) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.08.007 · Cited by 14
Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain
Travis, C. R., Francis, D. Y., Williams, D. C., & Waters, M. L. (2022) · Protein Science · doi:10.1002/pro.4533 · Cited by 14
Continuous Fluorescent Sirtuin Activity Assay Based on Fatty Acylated Lysines
Zessin, M., Meleshin, M., Hilscher, S., Schiene‐Fischer, C., Bařinka, C., Jung, M., & Schutkowski, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087416 · Cited by 14
A review of tasquinimod in the treatment of advanced prostate cancer
Heer, R., Williamson, S. C., & Hartley, A. (2013) · Drug Design Development and Therapy · doi:10.2147/dddt.s31500 · Cited by 14
The dark side of HDAC inhibition in ALS
Boutillier, A., Tzeplaeff, L., & Dupuis, L. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.02.039 · Cited by 14
Nash, B., Festa, L. K., Lin, C., & Meucci, O. (2019) · Brain Research · doi:10.1016/j.brainres.2019.146409 · Cited by 14
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Methylation muscles into transcription factor silencing
Bharathy, N., & Taneja, R. (2012) · Transcription · doi:10.4161/trns.20914 · Cited by 13
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Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling
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Minisini, M., Cricchi, E., & Brancolini, C. (2023) · Life · doi:10.3390/life14010020 · Cited by 13
Class IIa HDACs inhibitor TMP269 promotes M1 polarization of macrophages after spinal cord injury
Qi, X., & Wang, P. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.26446 · Cited by 12
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Rational Design and Development of HDAC Inhibitors for Breast Cancer Treatment
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Metadata
- Authors
- Lahm, A., Paolini, C., Pallaoro, M., Nardi, M. C., Jones, P., Neddermann, P., Sambucini, S., Bottomley, M. J., Lo Surdo, P., Carfı́, A., Koch, U., De Francesco, R., Steinkühler, C., & Gallinari, P.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Istituto di Ricerche di Biologia Molecolare, I.R.B.M., P. Angeletti, 00040 Pomezia, Italy
- Corresponding author
- Gallinari, P.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-30
- Volume
- 104
- Issue
- 44
- Pages
- 17335-17340
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2077257
- OpenAlex
- W2152631096
- Cited by
- 566
- References
- 36
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 40 · 2023: 15 · 2022: 32 · 2021: 33 · 2020: 32 · 2019: 37 · 2018: 31 · 2017: 29 · 2016: 31 · 2015: 44 · 2014: 29 · 2013: 39 · 2012: 34
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (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 › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- class IIa histone deacetylases, HDAC4, HDAC5, HDAC7, HDAC9, catalytic efficiency, histone deacetylase inhibitors, class I HDACs, catalytic tyrosine, enzyme evolution, substrate specificity
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Catalysis, Enzyme Activation, HeLa Cells, Histidine, Histone Deacetylases, Humans, Models, Molecular, Mutation, Substrate Specificity, Urochordata, Vertebrates, Protein Structure, Tertiary
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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