Selective class IIa HDAC inhibitors: myth or reality

Giorgio, Eros Di; Gagliostro, Enrico; Brancolini, Claudio

doi:10.1007/s00018-014-1727-8

Cited by 51 publications

(36 citation statements)

References 118 publications

(199 reference statements)

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“…We continued by testing the specific HDAC Class II inhibitors tubastatin A (150–500 nM; Class IIb, HDAC 6 inhibitor) 15 , and MC1568 (1 μM; Class IIa inhibitor) 2,16–19 . Acute tubastatin A (150 nM) bath application did not affect gamma oscillations in PPN neurons (n = 5) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus

Urbano

Bisagno

Mahaffey

et al. 2018

Sci Rep

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Epigenetic mechanisms (i.e., histone post-translational modification and DNA methylation) play a role in regulation of gene expression. The pedunculopontine nucleus (PPN), part of the reticular activating system, manifests intrinsic gamma oscillations generated by voltage-dependent, high threshold N- and P/Q-type Ca2+ channels. We studied whether PPN intrinsic gamma oscillations are affected by inhibition of histone deacetylation. We showed that, a) acute in vitro exposure to the histone deacetylation Class I and II inhibitor trichostatin A (TSA, 1 μM) eliminated oscillations in the gamma range, but not lower frequencies, b) pre-incubation with TSA (1 μM, 90–120 min) also decreased gamma oscillations, c) Ca2+ currents (ICa) were reduced by TSA, especially on cells with P/Q-type channels, d) a HDAC Class I inhibitor MS275 (500 nM), and a Class IIb inhibitor Tubastatin A (150–500 nM), failed to affect gamma oscillations, e) MC1568, a HDAC Class IIa inhibitor (1 μM), blocked gamma oscillations, and f) the effects of both TSA and MC1568 were blunted by blockade of CaMKII with KN-93 (1 μM). These results suggest a cell type specific effect on gamma oscillations when histone deacetylation is blocked, suggesting that gamma oscillations through P/Q-type channels modulated by CaMKII may be linked to processes related to gene transcription.

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Section: Resultsmentioning

confidence: 99%

Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus

Urbano

Bisagno

Mahaffey

et al. 2018

Sci Rep

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“…Even though class-IIa HDACs do not exhibit catalytic activity, they can act as platforms to recruit class-I enzymes (Lahm et al, 2007;Di Giorgio et al, 2015a). Hence, HDAC7 could influence epigenetic changes at the CDKN1A promoter both by recruiting co-repressors and by competing with co-activators for binding to MEF2 proteins.…”

Section: Discussionmentioning

confidence: 99%

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

Clocchiatti

Giorgio

Viviani

et al. 2015

Journal of Cell Science

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The myocyte enhancer factor 2 and histone deacetylase (MEF2-HDAC) axis is a master regulator of different developmental programs and adaptive responses in adults. In this paper, we have investigated the contribution of the axis to the regulation of epithelial morphogenesis, using 3D organotypic cultures of MCF10A cells as a model. We have demonstrated that MEF2 transcriptional activity is upregulated during acini formation, which coincides with exit from the proliferative phase. Upregulation of the transcription of MEF2 proteins is coupled to downregulation of HDAC7, which occurs independently from changes in mRNA levels, and proteasome-or autophagymediated degradation. During acini formation, the MEF2-HDAC axis contributes to the promotion of cell cycle exit, through the engagement of the CDK inhibitor CDKN1A. Only in proliferating cells can HDAC7 bind to the first intron of the CDKN1A gene, a region characterized by epigenetic markers of active promoters and enhancers. In cells transformed by the oncogene HER2 (ERBB2), acini morphogenesis is altered, MEF2 transcription is repressed and HDAC7 is continuously expressed. Importantly, reactivation of MEF2 transcriptional activity in these cells, through the use of a HER2 inhibitor or by enhancing MEF2 function, corrected the proliferative defect and re-established normal acini morphogenesis.

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“…The growing interest for HDAC6-selective inhibitors is related to the modulation of acetylation of non-histone regulatory proteins (α-tubulin) implicated in cancer initiation and progression. Previous studies have focused on how the deacetylation of tubulin affects cell migration, metastasis, angiogenesis, and stress–response pathways [35,36]. …”

Section: Hdac Classification and Their Physiological Rolesmentioning

confidence: 99%

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

Cosenza

Pozzi

2018

IJMS

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Histone deacetylases (HDACs) are master regulators of chromatin remodeling, acting as epigenetic regulators of gene expression. In the last decade, inhibition of HDACs has become a target for specific epigenetic modifications related to cancer development. Overexpression of HDAC has been observed in several hematologic malignancies. Therefore, the observation that HDACs might play a role in various hematologic malignancies has brought to the development of HDAC inhibitors as potential antitumor agents. Recently, the class IIb, HDAC6, has emerged as one potential selective HDACi. This isoenzyme represents an important pharmacological target for selective inhibition. Its selectivity may reduce the toxicity related to the off-target effects of pan-HDAC inhibitors. HDAC6 has also been studied in cancer especially for its ability to coordinate a variety of cellular processes that are important for cancer pathogenesis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Various studies of HDAC6 inhibitors alone and in combination with other agents provide strong scientific rationale for the evaluation of these new agents in the clinical setting of hematological malignancies. In this review, we describe the HDACs, their inhibitors, and the recent advances of HDAC6 inhibitors, their mechanisms of action and role in lymphoproliferative disorders.

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Selective class IIa HDAC inhibitors: myth or reality

Cited by 51 publications

References 118 publications

Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus

Class II histone deacetylases require P/Q-type Ca2+ channels and CaMKII to maintain gamma oscillations in the pedunculopontine nucleus

The MEF2–HDAC axis controls proliferation of mammary epithelial cells and acini formation in vitro

The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease

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