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The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPR mt . HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPR mt , innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPR mt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPR mt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPR mt ). Here the authors show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC), coordinates with the genome organizer DVE-1 to activate UPR mt and modulate mitochondrial homeostasis.

The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.

Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.

Histone acetylation is a pivotal epigenetic modification that controls chromatin structure and regulates gene expression. It plays an essential role in modulating zygotic transcription and cell lineage specification of developing embryos. While the outcomes of many inductive signals have been described to require enzymatic activities of histone acetyltransferases and deacetylases (HDACs), the mechanisms by which HDACs confine the utilization of the zygotic genome remain to be elucidated. Here, we show that histone deacetylase 1 (Hdac1) progressively binds to the zygotic genome from mid-blastula and onward. The recruitment of Hdac1 to the genome at blastula is instructed maternally. Cis -regulatory modules (CRMs) bound by Hdac1 possess epigenetic signatures underlying distinct functions. We highlight a dual function model of Hdac1 where Hdac1 not only represses gene expression by sustaining a histone hypoacetylation state on inactive chromatin, but also maintains gene expression through participating in dynamic histone acetylation–deacetylation cycles on active chromatin. As a result, Hdac1 maintains differential histone acetylation states of bound CRMs between different germ layers and reinforces the transcriptional program underlying cell lineage identities, both in time and space. Taken together, our study reveals a comprehensive role for Hdac1 during early vertebrate embryogenesis.

Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.

Background In breast cancer, the role of epigenetic alterations including modifications of the acetylation status of histones in carcinogenesis has been an important research focus during the last years. An increased deacetylation of histones leads to increased cell proliferation, cell migration, angiogenesis and invasion. Class 1 histone deacetylases (HDAC) seem to be most important during carcinogenesis. Methods The immunhistochemical expression of HDAC1, 2 and 3 was analyzed on tissue microarrays (TMAs) from 238 patients with primary breast cancer. We analyzed the nuclear staining intensity (negative, weak, moderate, strong) as well as the percentage of positive tumor cells and calculated the immunoreactivity score (0–12). Expression was correlated with clinicopathological parameters and patient survival. Results In this cohort, we found a differential positive expression of HDAC1, HDAC2 and HDAC3. HDAC2 and HDAC3 expression was significantly higher in less differentiated tumors: HDAC2 (n=207), p<0.001 and HDAC3 (n=220), p<0.001 and correlated with negative hormone receptor status: HDAC2 (n=206), p=0.02 and HDAC3 (n=219), p=0.04. Additionally, a high HDAC2 expression was significantly associated with an overexpression of HER2 (n=203, p=0.005) and the presence of nodal metastasis (n=200, p=0.04). HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p<0.001). Conclusion As a conclusion, our results show that the class-1 HDAC isoenzymes 1, 2 and 3 are differentially expressed in breast cancer. HDAC2 and HDAC3 are strongly expressed in subgroups of tumor with features of a more aggressive tumor type.

Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD + ) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body D-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.

Histone deacetylases (HDACs) belong to a family of enzymes that remove acetyl groups from the ɛ-amino of histone and nonhistone proteins. Additionally, HDACs participate in the genesis and development of cancer diseases as promising therapeutic targets to treat cancer. Therefore, in this work, we designed and evaluated a set of hydroxamic acid derivatives that contain a hydrophobic moiety as antiproliferative HDAC inhibitors. For the chemical structure design, in silico tools (molecular docking, molecular dynamic (MD) simulations, ADME/Tox properties were used to target Zn 2+ atoms and HDAC hydrophobic cavities. The most promising compounds were assayed in different cancer cell lines, including hepatocellular carcinoma (HepG2), pancreatic cancer (MIA PaCa-2), breast cancer (MCF-7 and HCC1954), renal cancer (RCC4-VHL and RCC4-VA) and neuroblastoma (SH-SY5Y). Molecular docking and MD simulations coupled to the MMGBSA approach showed that the target compounds have affinity for HDAC1, HDAC6 and HDAC8. Of all the compounds evaluated, YSL-109 showed the best activity against hepatocellular carcinoma (HepG2 cell line, IC 50  = 3.39 µM), breast cancer (MCF-7 cell line, IC 50  = 3.41 µM; HCC1954 cell line, IC 50  = 3.41 µM) and neuroblastoma (SH-SY5Y cell line, IC 50  = 6.42 µM). In vitro inhibition assays of compound YSL-109 against the HDACs showed IC 50 values of 259.439 µM for HDAC1, 0.537 nM for HDAC6 and 2.24 µM for HDAC8.

Key Points Epigenetic deregulation can underpin the onset and progression of several human diseases. The expression and/or function of histone deacetylases (HDACs) is often perturbed in cancer, neurological syndromes and immune disorders. HDACs can be effectively targeted using small-molecule chemical compounds, and more selective agents are currently being developed and further tested. Histones are not the only substrates of HDACs, and altered acetylation of diverse cellular proteins may be important in disease aetiology and the response to HDAC inhibitors. HDACs function as the catalytic subunits of large multiprotein complexes, and the molecular and biological consequences of HDAC inhibition need to be assessed in this context. HDAC inhibitors have been approved for the treatment of certain haematological malignancies and are being clinically evaluated alone and in combination with other agents for efficacy in other cancer settings, in neurological diseases and in immune disorders such as autoimmunity. Histone deacetylases (HDACs) are a class of epigenetic enzymes that remove acetyl groups from lysine residues on histones and other proteins. In this Review, the authors highlight the role of HDACs in cancer, neurological diseases and immune disorders, and discuss the development of small-molecule inhibitors. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is generated from sphingosine by sphingosine kinases (SPHKs) 1 and 2 and is metabolized to ∆2-hexadecenal (∆2-HDE) and ethanolamine phosphate by S1P lyase (S1PL) in mammalian cells. We have recently demonstrated the activation of nuclear SPHK2 and the generation of S1P in the nucleus of lung epithelial cells exposed to Pseudomonas aeruginosa. Here, we have investigated the nuclear localization of S1PL and the role of ∆2-HDE generated from S1P in the nucleus as a modulator of histone deacetylase (HDAC) activity and histone acetylation. Electron micrographs of the nuclear fractions isolated from MLE-12 cells showed nuclei free of ER contamination, and S1PL activity was detected in nuclear fractions isolated from primary lung bronchial epithelial cells and alveolar epithelial MLE-12 cells. Pseudomonasaeruginosa-mediated nuclear ∆2-HDE generation, and H3/H4 histone acetylation was attenuated by S1PL inhibitors in MLE-12 cells and human bronchial epithelial cells. In vitro, the addition of exogenous ∆2-HDE (100–10,000 nM) to lung epithelial cell nuclear preparations inhibited HDAC1/2 activity, and increased acetylation of Histone H3 and H4, whereas similar concentrations of S1P did not show a significant change. In addition, incubation of ∆2-HDE with rHDAC1 generated five different amino acid adducts as detected by LC-MS/MS; the predominant adduct being ∆2-HDE with lysine residues of HDAC1. Together, these data show an important role for the nuclear S1PL-derived ∆2-HDE in the modification of HDAC activity, histone acetylation, and chromatin remodeling in lung epithelial cells.