Identification of a Histone Deacetylase 8 Inhibitor through Drug Screenings Based on Machine Learning.

Histone deacetylase 8 (HDAC8) is a zinc-dependent HDAC that catalyzes the deacetylation of nonhistone proteins. It is involved in cancer development and HDAC8 inhibitors are promising candidates as anticancer agents. However, most reported HDAC8 inhibitors contain a hydroxamic acid moiety, which often causes mutagenicity. Therefore, we used machine learning for drug screening and attempted to identify non-hydroxamic acids as HDAC8 inhibitors. In this study, we established a prediction model based on the random forest (RF) algorithm for screening HDAC8 inhibitors because it exhibited the best predictive accuracy in the training dataset, including data generated by the synthetic minority over-sampling technique (SMOTE). Using the trained RF-SMOTE model, we screened the Osaka University library for compounds and selected 50 virtual hits. However, the 50 hits in the first screening did not show HDAC8-inhibitory activity. In the second screening, using the RF-SMOTE model, which was established by retraining the dataset including 50 inactive compounds, we identified non-hydroxamic acid 12 as an HDAC8 inhibitor with an IC50 of 842 nM. Interestingly, its IC50 values for HDAC1 and HDAC3-inhibitory activity were 38 and 12 µM, respectively, showing that compound 12 has high HDAC8 selectivity. Using machine learning, we expanded the chemical space for HDAC8 inhibitors and identified non-hydroxamic acid 12 as a novel HDAC8 selective inhibitor.

Evaluation and molecular docking study of two flavonoids from Oroxylum indicum (L.) Kurz and their semi-synthetic derivatives as histone deacetylase inhibitors.

Chrysin (5,7-dihydroxyflavone, 6) and galangin 3-methyl ether (5,7-dihydroxy-3-methoxy flavone, 7) were obtained from the leaves of Oroxylum indicum (L.) Kurz in 4% and 6% yields, respectively. Both compounds could act as pan-histone deacetylase (HDAC) inhibitors. Structural modification of these lead compounds provided thirty-eight derivatives which were further tested as HDAC inhibitors. Compounds 6b, 6c, and 6q were the most potent derivatives with the IC50 values of 97.29 ± 0.63 µM, 91.71 ± 0.27 µM, and 96.87 ± 0.45 µM, respectively. Molecular docking study indicated the selectivity of these three compounds toward HDAC8 and the test against HDAC8 showed IC50 values in the same micromolar range. All three compounds were further evaluated for the anti-proliferative activity against HeLa and A549 cell lines. Compound 6q exhibited the best activity against HeLa cell line with the IC50 value of 13.91 ± 0.34 µM. Moreover, 6q was able to increase the acetylation level of histone H3. These promising HDAC inhibitors deserve investigation as chemotherapeutic agents for treating cancer.

Inhibition of Heat Shock-Induced H3K9ac Reduction Sensitizes Cancer Cells to Hyperthermia.

Heat stress, clinically known as hyperthermia, is a promising adjunctive modality in cancer treatment. However, the efficacy of hyperthermia as a monotherapy is limited and the underlying mechanism remains poorly understood. Targeting histone modifications is an emerging strategy for cancer therapy, but little is known regarding the role of heat stress in altering these modifications. Here, we report that heat shock inhibits H3K9 acetylation (H3K9ac) via histone deacetylase 6 (HDAC6) regulation. Heat shock inhibits the interaction between HDAC6 and heat shock protein 90 (HSP90), enhances nuclear localization of HDAC6, and promotes HDAC6 phosphorylation, which is regulated by protein phosphatase 2A (PP2A). Combining hyperthermia with HDAC inhibitors vorinostat or panobinostat leads to better anti-cancer effects compared to monotherapy. KEAP1 and DPP7 as genes affected by heat-induced inhibition of H3K9ac, and combining them with hyperthermia can better induce apoptosis in tumor cells. This study reveals previously unknown mechanisms of H3K9ac decreased by heat shock in cancer cells and highlights a potential combinational therapy involving hyperthermia and targeting of these new mechanisms.

Chemoproteomic target deconvolution reveals Histone Deacetylases as targets of (R)-lipoic acid.

Lipoic acid is an essential enzyme cofactor in central metabolic pathways. Due to its claimed antioxidant properties, racemic (R/S)-lipoic acid is used as a food supplement but is also investigated as a pharmaceutical in over 180 clinical trials covering a broad range of diseases. Moreover, (R/S)-lipoic acid is an approved drug for the treatment of diabetic neuropathy. However, its mechanism of action remains elusive. Here, we performed chemoproteomics-aided target deconvolution of lipoic acid and its active close analog lipoamide. We find that histone deacetylases HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, and HDAC10 are molecular targets of the reduced form of lipoic acid and lipoamide. Importantly, only the naturally occurring (R)-enantiomer inhibits HDACs at physiologically relevant concentrations and leads to hyperacetylation of HDAC substrates. The inhibition of HDACs by (R)-lipoic acid and lipoamide explain why both compounds prevent stress granule formation in cells and may also provide a molecular rationale for many other phenotypic effects elicited by lipoic acid.

Genome-Wide Identification of Histone Deacetylases and Their Roles Related with Light Response in Tartary Buckwheat (Fagopyrum tataricum).

Histone deacetylases (HDACs), known as histone acetylation erasers, function crucially in plant growth and development. Although there are abundant reports focusing on HDACs of Arabidopsis and illustrating their important roles, the knowledge of HDAC genes in Tartary buckwheat (Polygonales Polygonaceae Fagopyrum tataricum (L.) Gaertn) is still scarce. In the study, a total of 14 HDAC genes were identified and divided into three main groups: Reduced Potassium Dependency-3/His-52 tone Deacetylase 1 (RPD3/HDA1), Silent Information Regulator 2 (SIR2), and the plant-53 specific HD2. Domain and motif composition analysis showed there were conserved domains and motifs in members from the same subfamilies. The 14 FtHDACs were distributed asymmetrically on 7 chromosomes, with three segmental events and one tandem duplication event identified. The prediction of the cis-element in promoters suggested that FtHDACs probably acted in numerous biological processes including plant growth, development, and response to environmental signals. Furthermore, expression analysis based on RNA-seq data displayed that all FtHDAC genes were universally and distinctly expressed in diverse tissues and fruit development stages. In addition, we found divergent alterations in FtHDACs transcript abundance in response to different light conditions according to RNA-seq and RT-qPCR data, indicating that five FtHDACs might be involved in light response. Our findings could provide fundamental information for the HDAC gene family and supply several targets for future function analysis of FtHDACs related with light response of Tartary buckwheat.

Selectivity of Hydroxamate- and Difluoromethyloxadiazole-Based Inhibitors of Histone Deacetylase 6 In Vitro and in Cells.

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family of enzymes due to its complex domain organization and cytosolic localization. Experimental data point toward the therapeutic use of HDAC6-selective inhibitors (HDAC6is) for use in both neurological and psychiatric disorders. In this article, we provide side-by-side comparisons of hydroxamate-based HDAC6is frequently used in the field and a novel HDAC6 inhibitor containing the difluoromethyl-1,3,4-oxadiazole function as an alternative zinc-binding group (compound 7). In vitro isotype selectivity screening uncovered HDAC10 as a primary off-target for the hydroxamate-based HDAC6is, while compound 7 features exquisite 10,000-fold selectivity over all other HDAC isoforms. Complementary cell-based assays using tubulin acetylation as a surrogate readout revealed approximately 100-fold lower apparent potency for all compounds. Finally, the limited selectivity of a number of these HDAC6is is shown to be linked to cytotoxicity in RPMI-8226 cells. Our results clearly show that off-target effects of HDAC6is must be considered before attributing observed physiological readouts solely to HDAC6 inhibition. Moreover, given their unparalleled specificity, the oxadiazole-based inhibitors would best be employed either as research tools in further probing HDAC6 biology or as leads in the development of truly HDAC6-specific compounds in the treatment of human disease states.

The activation of histone deacetylases 4 prevented endothelial dysfunction: A crucial mechanism of HuangqiGuizhiWuwu Decoction in improving microcirculation dysfunction in diabetes.

ETHNOPHARMACOLOGICAL RELEVANCE: The regulation of epigenetic factors is considered a crucial target for solving complex chronic diseases such as cardio-cerebrovascular diseases. HuangqiGuizhiWuwu Decoction (HGWWD), a classic Chinese prescription, is mainly used to treat various vascular diseases. Although our previous studies reported that HGWWD could effectively prevent vascular dysfunction in diabetic rodent models, the precise mechanism is still elusive. AIM OF THE STUDY: In this study, we investigated the epigenetic mechanisms of modulating the damage of vascular endothelial cells in diabetes by HGWWD. METHODS: We first analyzed common active components of HGWWD by using HPLC-Q-TOF-MS/MS analysis, and predicted the isoforms of histone deacetylase (HDAC) that can potentially combine the above active components by systems pharmacology. Next, we screened the involvement of specific HDAC isoforms in the protective effect of HGWWD on vascular injury by using pharmacological blockade combined with the evaluation of vascular function in vivo and in vitro. RESULTS: Firstly, HDAC1, HDAC2, HDAC3, HDAC4, HDAC6, HDAC7, SIRT2, and SIRT3 have been implicated with the possibility of binding to the thirty-one common active components in HGWWD. Furthermore, the protective effect of HGWWD is reversed by both TSA (HDAC inhibitor) and MC1568 (class II HDAC inhibitor) on vascular impairment accompanied by reduced aortic HDAC activity in STZ mice. Finally, inhibition of HDAC4 blocked the protective effect of HGWWD on microvascular and endothelial dysfunction in diabetic mice. CONCLUSIONS: These results prove the key role of HDAC4 in diabetes-induced microvascular dysfunction and underlying epigenetic mechanisms for the protective effect of HGWWD in diabetes.

Low expression of the intestinal metabolite butyric acid and the corresponding memory pattern regulate HDAC4 to promote apoptosis in rat hippocampal neurons.

After intensive research on the gut-brain axis, intestinal dysbiosis is considered to be one of the important pathways of cognitive decline. Microbiota transplantation has long been thought to reverse the behavioral changes in the brain caused by colony dysregulation, but in our study, microbiota transplantation seemed to improve only behavioral brain function, and there was no reasonable explanation for the high level of hippocampal neuron apoptosis that remained. Butyric acid is one of the short-chain fatty acids of intestinal metabolites and is mainly used as an edible flavoring. It is commonly used in butter, cheese and fruit flavorings, and is a natural product of bacterial fermentation of dietary fiber and resistant starch in the colon, acting similarly to the small-molecule HDAC inhibitor TSA. The effect of butyric acid on HDAC levels in hippocampal neurons in the brain remains unclear. Therefore, this study used rats with low bacterial abundance, conditional knockout mice, microbiota transplantation, 16S rDNA amplicon sequencing, and behavioral assays to demonstrate the regulatory mechanism of short-chain fatty acids on the acetylation of hippocampal histones. The results showed that disturbance of short-chain fatty acid metabolism led to high HDAC4 expression in the hippocampus and regulated H4K8ac, H4K12ac, and H4K16ac to promote increased neuronal apoptosis. However, microbiota transplantation did not change the pattern of low butyric acid expression, resulting in maintained high HDAC4 expression in hippocampal neurons with continued neuronal apoptosis. Overall, our study shows that low levels of butyric acid in vivo can promote HDAC4 expression through the gut-brain axis pathway, leading to hippocampal neuronal apoptosis, and demonstrates that butyric acid has great potential value for neuroprotection in the brain. In this regard, we suggest that patients with chronic dysbiosis should pay attention to changes in the levels of SCFAs in their bodies, and if deficiencies occur, they should be promptly supplemented through diet and other means to avoid affecting brain health.

Jatrorrhizine ameliorates Schwann cell myelination via inhibiting HDAC3 ability to recruit Atxn2l for regulating the NRG1-ErbB2-PI3K-AKT pathway in diabetic peripheral neuropathy mice.

Diabetic peripheral neuropathy (DPN) is a chronic complication associated with nerve dysfunction and uncontrolled hyperglycemia. Unfortunately, due to its complicated etiology, there has been no successful therapy for DPN. Our research recently revealed that jatrorrhizine (JAT), one of the active constituents of Rhizoma Coptidis, remarkably ameliorated DPN. This work highlighted the potential mechanism through which JAT relieves DPN using db/db mice. The results indicated that JAT treatment significantly decreased the threshold for thermal and mechanical stimuli and increased nerve conduction velocity. Histopathological analysis revealed that JAT significantly increased the number of sciatic nerve fibers and axons, myelin thickness, and axonal diameters. Additionally, JAT markedly elevated the expression of myelination-associated proteins (MBP, MPZ, and Pmp22). The screening of histone deacetylases (HDAC) determined that histone deacetylase 3 (HDAC3) is an excellent target for JAT-induced myelination enhancement. Liquid chromatography-mass spectrometry-(MS)/MS and coimmunoprecipitation analyses further confirmed that HDAC3 antagonizes the NRG1-ErbB2-PI3K-AKT signaling axis by interacting with Atxn2l to augment SCs myelination. Thus, JAT ameliorates SCs myelination in DPN mice via inhibiting the recruitment of Atxn2l by HDAC3 to regulate the NRG1-ErbB2-PI3K-AKT pathway.

METTL3-mediated N6-methyladenosine modification and HDAC5/YY1 promote IFFO1 downregulation in tumor development and chemo-resistance.

Ovarian cancer (OC) is a malignant tumor that seriously threatens women's health. Due to the difficulty of early diagnosis, most patients exhibit advanced disease or peritoneal metastasis at diagnosis. We discovered that IFFO1 is a novel tumor suppressor, but its role in tumorigenesis, development and chemoresistance is unknown. In this study, IFFO1 levels were downregulated across cancers, leading to the acceleration of tumor development, metastasis and/or cisplatin resistance. Overexpression of IFFO1 inhibited the translocation of ß-catenin to the nucleus and decreased tumor metastasis and cisplatin resistance. Furthermore, we demonstrated that IFFO1 was regulated at both the transcriptional and posttranscriptional levels. At the transcriptional level, the recruitment of HDAC5 inhibited IFFO1 expression, which is mediated by the transcription factor YY1, and the METTL3/YTHDF2 axis regulated the mRNA stability of IFFO1 in an m6A-dependent manner. Mice injected with IFFO1-overexpressing cells had lower ascites volumes and tumor weights throughout the peritoneal cavity than those injected with parental cells expressing the vector control. In conclusion, we demonstrated that IFFO1 is a novel tumor suppressor that inhibits tumor metastasis and reverses drug resistance in ovarian cancer. IFFO1 was downregulated at both the transcriptional level and posttranscriptional level by histone deacetylase and RNA methylation, respectively, and the IFFO1 signaling pathway was identified as a potential therapeutic target for cancer.

Histone deacetylase CsHDA6 mediates the regulated formation of the anti-insect metabolite α-farnesene in tea (Camellia sinensis).

α-Farnesene accumulated in tea plants following infestations by most insects, and mechanical wounding is the common factor. However, the specific mechanism underlying the wounding-regulated accumulation of α-farnesene in tea plants remains unclear. In this study, we observed that histone deacetylase inhibitor treatment induced the accumulation of α-farnesene. The histone deacetylase CsHDA6 interacted directly with CsMYC2, which was an important transcription factor in the jasmonic acid (JA) pathway, and co-regulated the expression of the key α-farnesene synthesis gene CsAFS. Wounding caused by insect infestation affected CsHDA6 production at the transcript and protein levels, while also inhibited the binding of CsHDA6 to the CsAFS promoter. The resulting increased acetylation of histones H3/H4 in CsAFS enhanced the expression of CsAFS and the accumulation of α-farnesene. In conclusion, our study demonstrated the effect of histone acetylation on the production of tea plant HIPVs and revealed the importance of the CsHDA6-CsMYC2 transcriptional regulatory module.

miR-3,178 contributes to the therapeutic action of baicalein against hepatocellular carcinoma cells via modulating HDAC10.

Hepatocellular carcinoma (HCC) is the most common type of hepatic malignancies with high mortality and poor prognosis. Baicalein, one of the major and bioactive flavonoids isolated from Scutellaria baicalensis Georgi, which is reported to have anti-proliferation effect in varying cancers, including HCC, whose underlying molecular mechanism is still largely unknown. In this study, we found that baicalein significantly inhibited proliferation and colony formation, blocked cell cycle, and promoted apoptosis in HCC cells MHCC-97H and SMMC-7721 in vitro and reduced tumor volume and weight in vivo. Increased microRNA (miR)-3,178 levels and decreased histone deacetylase 10 (HDAC10) expression were found in cells treated with baicalein and in patients' HCC tissues. HDAC10 was identified as a target gene of miR-3,178 by luciferase activity and western blot. Both baicalein treatment and overexpression of miR-3,178 could downregulate HDAC10 protein expression and inactivated AKT, MDM2/p53/Bcl2/Bax and FoxO3α/p27/CDK2/Cyclin E1 signal pathways. Not only that, knockdown of miR-3,178 could partly abolish the effects of baicalein and the restoration of HDAC10 could abated miR-3,178-mediated role in HCC cells. Collectively, baicalein inhibits cell viability, blocks cell cycle, and induces apoptosis in HCC cells by regulating the miR-3,178/HDAC10 pathway. This finding indicated that baicalein might be promising for treatment of HCC.

HISTONE DEACETYLASE 9 transduces heat signal in plant cells.

Heat stress limits plant growth, development, and crop yield, but how plant cells precisely sense and transduce heat stress signals remains elusive. Here, we identified a conserved heat stress response mechanism to elucidate how heat stress signal is transmitted from the cytoplasm into the nucleus for epigenetic modifiers. We demonstrate that HISTONE DEACETYLASE 9 (HDA9) transduces heat signals from the cytoplasm to the nucleus to play a positive regulatory role in heat responses in Arabidopsis. Heat specifically induces HDA9 accumulation in the nucleus. Under heat stress, the phosphatase PP2AB'ß directly interacts with and dephosphorylates HDA9 to protect HDA9 from 26S proteasome-mediated degradation, leading to the translocation of nonphosphorylated HDA9 to the nucleus. This heat-induced enrichment of HDA9 in the nucleus depends on the nucleoporin HOS1. In the nucleus, HDA9 binds and deacetylates the target genes related to signaling transduction and plant development to repress gene expression in a transcription factor YIN YANG 1-dependent and -independent manner, resulting in rebalance of plant development and heat response. Therefore, we uncover an HDA9-mediated positive regulatory module in the heat shock signal transduction pathway. More important, this cytoplasm-to-nucleus translocation of HDA9 in response to heat stress is conserved in wheat and rice, which confers the mechanism significant implication potential for crop breeding to cope with global climate warming.

The short-chain fatty acid butyrate accelerates vascular calcification via regulation of histone deacetylases and NF-κB signaling.

Recent studies have shown that short-chain fatty acids (SCFAs), primarily acetate, propionate and butyrate, play a crucial role in the pathogenesis of cardiovascular disease. Whether SCFAs regulate vascular calcification, a common pathological change in cardiovascular tissues, remains unclear. This study aimed to investigate the potential role of SCFAs in vascular calcification. Using cellular and animal models of vascular calcification, we showed that butyrate significantly enhanced high phosphate (Pi)-induced calcification and osteogenic transition of vascular smooth muscle cells (VSMC) in vitro, whereas acetate and propionate had no effects. Subsequent studies confirmed that butyrate significantly promoted high Pi-induced aortic ring calcification ex vivo and high dose vitamin D3 (vD3)-induced mouse vascular calcification in vivo. Mechanistically, butyrate significantly inhibited histone deacetylase (HDAC) expression in VSMCs, and a pan HDAC inhibitor Trichostatin A showed similar inductive effects on calcification and osteogenic transition of VSMCs to butyrate. In addition, the SCFA sensing receptors Gpr41 and Gpr109a were primarily expressed by VSMCs, and butyrate induced the rapid activation of NF-κB, Wnt and Akt signaling in VSMCs. Intriguingly, the NF-κB inhibitor SC75741 significantly attenuated butyrate-induced calcification and the osteogenic gene Msx2 expression in VSMCs. We showed that knockdown of Gpr41 but not Gpr109a attenuated butyrate-induced VSMC calcification. This study reveals that butyrate accelerates vascular calcification via its dual effects on HDAC inhibition and NF-κB activation. Our data provide novel insights into the role of microbe-host interaction in vascular calcification, and may have implications for the development of potential therapy for vascular calcification.

The chromatin remodeler BRAHMA recruits HISTONE DEACETYLASE6 to regulate root growth inhibition in response to phosphate starvation in Arabidopsis.

Plasticity in root system architecture (RSA) allows plants to adapt to changing nutritional status in the soil. Phosphorus availability is a major determinant of crop yield, and RSA remodeling is critical to increasing the efficiency of phosphorus acquisition. Although substantial progress has been made in understanding the signaling mechanism driving phosphate starvation responses in plants, whether and how epigenetic regulatory mechanisms contribute is poorly understood. Here, we report that the Switch defective/sucrose non-fermentable (SWI/SNF) ATPase BRAHMA (BRM) is involved in the local response to phosphate (Pi) starvation. The loss of BRM function induces iron (Fe) accumulation through increased LOW PHOSPHATE ROOT1 (LPR1) and LPR2 expression, reducing primary root length under Pi deficiency. We also demonstrate that BRM recruits the histone deacetylase (HDA) complex HDA6-HDC1 to facilitate histone H3 deacetylation at LPR loci, thereby negatively regulating local Pi deficiency responses. BRM is degraded under Pi deficiency conditions through the 26 S proteasome pathway, leading to increased histone H3 acetylation at the LPR loci. Collectively, our data suggest that the chromatin remodeler BRM, in concert with HDA6, negatively regulates Fe-dependent local Pi starvation responses by transcriptionally repressing the RSA-related genes LPR1 and LPR2 in Arabidopsis thaliana.

Genome-Wide Analysis of the HDAC Gene Family and Its Functional Characterization at Low Temperatures in Tartary Buckwheat (Fagopyrum tataricum).

Histone deacetylases (HDACs), widely found in various types of eukaryotic cells, play crucial roles in biological process, including the biotic and abiotic stress responses in plants. However, no research on the HDACs of Fagopyrum tataricum has been reported. Here, 14 putative FtHDAC genes were identified and annotated in Fagopyrum tataricum. Their gene structure, motif composition, cis-acting elements, phylogenetic relationships, protein structure, alternative splicing events, subcellular localization and gene expression pattern were investigated. The gene structure showed FtHDACs were classified into three subfamilies. The promoter analysis revealed the presence of various cis-acting elements responsible for hormone, abiotic stress and developmental regulation for the specific induction of FtHDACs. Two duplication events were identified in FtHDA6-1, FtHDA6-2, and FtHDA19. The expression patterns of FtHDACs showed their correlation with the flavonoid synthesis pathway genes. In addition, alternative splicing, mRNA enrichment profiles and transgenic analysis showed the potential role of FtHDACs in cold responses. Our study characterized FtHDACs, providing a candidate gene family for agricultural breeding and crop improvement.

Downregulation of HDAC9 by the ketone metabolite ß-hydroxybutyrate suppresses vascular calcification.

Vascular calcification is an actively regulated process resembling bone formation and contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD). However, an effective therapy for vascular calcification is still lacking. The ketone body ß-hydroxybutyrate (BHB) has been demonstrated to have health-promoting effects including anti-inflammation and cardiovascular protective effects. However, whether BHB protects against vascular calcification in CKD remains unclear. In this study, Alizarin Red staining and calcium content assay showed that BHB reduced calcification of vascular smooth muscle cells (VSMCs) and arterial rings. Of note, compared with CKD patients without thoracic calcification, serum BHB levels were lower in CKD patients with thoracic calcification. Supplementation with 1,3-butanediol (1,3-B), the precursor of BHB, attenuated aortic calcification in CKD rats and VitD3-overloaded mice. Furthermore, RNA-seq analysis revealed that BHB downregulated HDAC9, which was further confirmed by RT-qPCR and western blot analysis. Both pharmacological inhibition and knockdown of HDAC9 attenuated calcification of human VSMCs, while overexpression of HDAC9 exacerbated calcification of VSMCs and aortic rings, indicating that HDAC9 promotes vascular calcification under CKD conditions. Of note, BHB treatment antagonized HDAC9-induced vascular calcification. In addition, HDAC9 overexpression activated the NF-κB signaling pathway and inhibition of NF-κB attenuated HDAC9-induced VSMC calcification, suggesting that HDAC9 promotes vascular calcification via activation of NF-κB. In conclusion, our study demonstrates that BHB supplementation inhibits vascular calcification in CKD via modulation of the HDAC9-dependent NF-κB signaling pathway. Moreover, we unveil a crucial mechanistic role of HDAC9 in vascular calcification under CKD conditions; thus, nutritional intervention or pharmacological approaches to enhance BHB levels could act as promising therapeutic strategies to target HDAC9 for the treatment of vascular calcification in CKD. © 2022 The Pathological Society of Great Britain and Ireland.

A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals.

The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (α/ß-hydrolase domain containing protein # 14B) as a novel KDAC and showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A to yield acetyl-coenzyme-A, thereby, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics and metabolomics analysis. We found from these complementary experiments in vivo that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.

Phosphorus containing analogues of SAHA as inhibitors of HDACs.

Histone deacetylases (HDACs) are a family of enzymes responsible for regulating DNA transcription by modulating its binding to histone proteins. HDACs are overexpressed in several types of cancers and are recognised as drug targets. Vorinostat, or suberanilohydroxamic acid (SAHA), is an histone deacetylase (HDAC) inhibitor with a hydroxamic acid as a zinc-binding group (ZBG), and it has been FDA approved for the treatment of T-cell lymphoma. In this work, phosphorus-based SAHA analogues were synthesised to assess their zinc-binding effectiveness compared to the hydroxamic acid of SAHA. Specifically, we examined phosphate, phosphoramidate and phosphorothiolate groups as isosteres of the canonical hydroxamic acid motif of conventional HDAC inhibitors. The compounds were screened for binding to HDAC enzymes from HeLa cell lysate. The most potent derivatives were then screened against HDAC3 and HDAC8 isoforms. HDAC inhibition assays demonstrated that these phosphorus-based SAHA analogs exhibited slow binding to HDACs but with greater potency than phosphonate SAHA analogs examined previously. All compounds inhibited HDACs, the most potent having an IC50 of 50 µM.

Natural Bioactive Compounds Targeting Histone Deacetylases in Human Cancers: Recent Updates.

Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene's expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could prevent and treat various human cancers. Accordingly, the present study aimed to evaluate the pharmacodynamic action of different natural compounds extracted from medicinal plants against the enzymatic activity of HDAC.