Role Of Histone Deacetylases Research Articles

Role of the Histone Deacetylase Family in Lipid Metabolism: Structural Specificity and Functional Diversity.

Lipids play crucial roles in signal transduction. Lipid metabolism is associated with several transcriptional regulators, including peroxisome proliferator activated receptor γ, sterol regulatory element-binding protein 1, and acetyl-CoA carboxylase. In recent years, increasing evidence has suggested that members of the histone deacetylase (HDAC) family play key roles in lipid metabolism. However, the mechanisms by which each member of this family regulates lipid metabolism remain unclear. This review discusses the latest research on the roles played by HDACs in fat metabolism. The role of HDACs in obesity, diabetes, and atherosclerosis has also been discussed. In addition, the interaction of HDACs with the gut microbiome and circadian rhythm has been reviewed, and the future development trend in HDACs has been predicted, which may potentiate therapeutic application of targeted HDACs in related metabolic diseases.

Role of HDAC3 in the epithelial-mesenchymal transition of retinal pigment epithelium cells: Implications for proliferative vitreoretinopathy

Proliferative vitreoretinopathy(PVR) is a type of fibrotic eye disease with a poor clinical prognosis. Increasing evidence has shown that the primary pathological mechanism of PVR is the epithelial-mesenchymal transition(EMT) of retinal pigment epithelium(RPE) cells. Histone deacetylase 3(HDAC3) is a crucial enzyme involved in regulating the acetylation level of proteins. Several studies have reported associations between HDAC3 levels and EMT in various tumors; however, the specific effect of HDAC3 on PVR remains largely unknown. The current study found that HDAC3 was highly expressed in both human PVR membranes and experimental PVR. In vivo, silencing HDAC3 in RPE cells reduced their ability to develop experimental PVR through suppression of EMT. In vitro, inhibition of HDAC3 in RPE cells suppressed EGF-mediated cell proliferation, migration, and EMT. Additionally, overexpression of HDAC3 in RPE cells promoted cell proliferation, migration, and EMT. Mechanistically, the results of chromatin immunoprecipitation(ChIP) and luciferase assays revealed a direct binding of the transcription factor MAZ to the promoter region of HDAC3, thereby promoting its transcription. Furthermore, It was demonstrated that HDAC3 facilitated EMT by interacting with AKT and contributing to its deacetylation. In summary, our findings indicated the involvement of HDAC3 in the EMT of RPE cells, as well as its role in PVR through the regulation of the AKT pathway. These results suggested that targeting HDAC3 could be a potential strategy for preventing and treating PVR.

Expression of Concern: A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs.

Expression of Concern: A Novel Role for Histone Deacetylase 6 in the Regulation of the Tolerogenic STAT3/IL-10 Pathway in APCs.

Suppression of SlHDT1 expression increases fruit yield and decreases drought and salt tolerance in tomato.

Histone deacetylation, one of most important types of post-translational modification, plays multiple indispensable roles in plant growth and development and abiotic stress responses. However, little information about the roles of histone deacetylase in regulating inflorescence architecture, fruit yield, and stress responses is available in tomato. Functional characterization revealed that SlHDT1 participated in the control of inflorescence architecture and fruit yield by regulating auxin signalling, and influenced tolerance to drought andsalt stresses by governing abscisic acid (ABA) signalling. More inflorescence branches and higher fruit yield, which were influenced by auxin signalling, were observed in SlHDT1-RNAi transgenic plants. Moreover, tolerance to drought andsalt stresses was decreased in SlHDT1-RNAi transgenic lines compared with the wild type (WT). Changes in parameters related to the stress response, including decreases in survival rate, chlorophyll content, relative water content (RWC), proline content, catalase (CAT) activity and ABA content and an increase in malonaldehyde (MDA) content, were observed in SlHDT1-RNAi transgenic lines. In addition, the RNA-seq analysis revealed varying degrees of downregulation for genes such as the stress-related genes SlABCC10 and SlGAME6 and the pathogenesis-related protein P450 gene SlCYP71A1, and upregulation of the pathogenesis-related protein P450 genes SlCYP94B1, SlCYP734A7 and SlCYP94A2 in SlHDT1-RNAi transgenic plants, indicating that SlHDT1 plays an important role in the response to biotic and abiotic stresses by mediating stress-related gene expression. In summary, the data suggest that SlHDT1 plays essential roles in the regulation of inflorescence architecture and fruit yield and in the response to drought andsalt stresses.

Epigenetic regulation of Nrf2-Mediated angiogenesis in diabetic foot ulcer progression: Role of histone deacetylases

Nuclear factor E2-related factor 2 (Nrf2), a redox-sensitive transcription factor, regulates proangiogenic mediators, and antioxidant and detoxification enzymes. However, hitherto its regulation in the progression of DFU was poorly examined. The regulation of Nrf2 has been reported to be affected by various factors, including histone deacetylase (HDACs) and DNA methylation. The present study aimed to profile all classes of HDACs and correlate them with Nrf2 and angiogenic markers in the tissue biopsies of different grades of DFU patients (n = 20 in each grade). The gene expression profile of Nrf2 and its downstream targets, angiogenic markers, and all classes of HDACs were assessed using qPCR. Spearman's correlation was performed to analyze the correlation of HDACs with Nrf2 and its downstream targets along with angiogenic markers. We observed a progressive decrease in the gene expression of Nrf2 and angiogenic markers such as VEGF, HIF-1α, and SDF-1α and also an increase in the TSP-2 expression in different grades of DFU. In parallel, a significant downregulation of HDAC2/8 and SIRT1/2/4 has been observed in various grades of DFU subjects. On the other hand, HDAC1/3/4/11 and SIRT3/5/6/7 showed upregulation in different grades of DFU and the maximum increase was observed in Grade 3 patients. A significant negative correlation between Nrf2 and HDAC4, angiogenic markers, and HDAC4 suggested the pivotal role of the HDAC4-regulated Nrf2-mediated angiogenesis among DFU subjects. We have generated a first line of evidence on the epigenetic regulation of Nrf2 and its correlation with angiogenesis in the progression of diabetic foot ulcers.

The Role of Histone Deacetylases in NLRP3 Inflammasomesmediated Epilepsy.

Epilepsy is one of the most common brain disorders that not only causes death worldwide, but also affects the daily lives of patients. Previous studies have revealed that inflammation plays an important role in the pathophysiology of epilepsy. Activation of inflammasomes can promote neuroinflammation by boosting the maturation of caspase-1 and the secretion of various inflammatory effectors, including chemokines, interleukins, and tumor necrosis factors. With the in-depth research on the mechanism of inflammasomes in the development of epilepsy, it has been discovered that NLRP3 inflammasomes may induce epilepsy by mediating neuronal inflammatory injury, neuronal loss and blood-brain barrier dysfunction. Therefore, blocking the activation of the NLRP3 inflammasomes may be a new epilepsy treatment strategy. However, the drugs that specifically block NLRP3 inflammasomes assembly has not been approved for clinical use. In this review, the mechanism of how HDACs, an inflammatory regulator, regulates the activation of NLRP3 inflammasome is summarized. It helps to explore the mechanism of the HDAC inhibitors inhibiting brain inflammatory damage so as to provide a potential therapeutic strategy for controlling the development of epilepsy.

Effects of Etanercept on Experimental Osteoarthritis in Rats: Role of Histone Deacetylases.

Mounting evidence suggests that histone deacetylases (HDAC) inhibitors reduce cartilage destruction in animal models of osteoarthritis (OA). Tumor necrosis factor (TNF)-α-blocking treatment for OA may provide effective joint protection by slowing joint damage. To investigate the effects of intraperitoneal administration of etanercept (a TNF-α inhibitor) on OA development in rats and changes in the nociceptive behavior of rats and expression of HDACs, RUNX2, and MMP13 in cartilage. Induction of OA in Wistar rats was accomplished through anterior cruciate ligament transection (ACLT). One or five milligrams (mg) of etanercept was administered intraperitoneally for 5 consecutive weeks after ACLT to the ACLT + etanercept (1 and 5 mg/kg) groups. Nociceptive behavior and changes in knee joint width were analyzed. Cartilage was evaluated histologically and immunohistochemically. ACLT + etanercept significantly improved mechanical allodynia and weight-bearing distribution compared to ACLT alone. In OA rats treated with etanercept, cartilage degeneration and synovitis were significantly less pronounced than those in ACLT rats. OA-affected cartilage also showed reduced expression of HDAC 6, 7, RUNX-2, and MMP-13 in response to etanercept but increased expression of HDAC4. Our study demonstrated that etanercept therapy (1) attenuated the development of OA and synovitis in rats, (2) reduced nociception, and (3) regulated chondrocyte metabolism, possibly by inhibiting cell HDAC6 and HDAC7, RUNX2, and MMP13 and increasing HDAC4 expression. Based on new evidence, etanercept may have therapeutic potential in OA.

Role of histone deacetylases and sirtuins in the ischaemic stroke: a protocol for a systematic review and meta-analysis of animal studies

BackgroundStroke is a major cause of global mortality and disability. Currently, the treatment of acute ischaemic stroke through reperfusion has posed several challenges, raising the need for complementary options to...

Innate Immune Evasion of PRRSV nsp11 through Degradation of the HDAC2 by Its Endoribonuclease Activity.

Porcine reproductive and respiratory syndrome virus (PRRSV), a member of the Arteriviridae family, represents a persistent menace to the global pig industry, causing reproductive failure and respiratory disease in pigs. In this study, we delved into the role of histone deacetylases (HDAC2) during PRRSV infection. Our findings revealed that HDAC2 expression is downregulated upon PRRSV infection. Notably, suppressing HDAC2 activity through specific small interfering RNA led to an increase in virus production, whereas overexpressing HDAC2 effectively inhibited PRRSV replication by boosting the expression of IFN-regulated antiviral molecules. Furthermore, we identified the virus's nonstructural protein 11 (nsp11) as a key player in reducing HDAC2 levels. Mutagenic analyses of PRRSV nsp11 revealed that its antagonistic effect on the antiviral activity of HDAC2 is dependent on its endonuclease activity. In summary, our research uncovered a novel immune evasion mechanism employed by PRRSV, providing crucial insights into the pathogenesis of this virus and guiding the development of innovative prevention strategies against PRRSV infection.

Roles of Histone Deacetylase 4 in the Inflammatory and Metabolic Processes.

Histone deacetylase 4 (HDAC4), a class IIa HDAC, has gained attention as a potential therapeutic target in treating inflammatory and metabolic processes based on its essential role in various biological pathways by deacetylating non-histone proteins, including transcription factors. The activity of HDAC4 is regulated at the transcriptional, post-transcriptional, and post-translational levels. The functions of HDAC4 are tissue-dependent in response to endogenous and exogenous factors and their substrates. In particular, the association of HDAC4 with non-histone targets, including transcription factors, such as myocyte enhancer factor 2, hypoxia-inducible factor, signal transducer and activator of transcription 1, and forkhead box proteins, play a crucial role in regulating inflammatory and metabolic processes. This review summarizes the regulatory modes of HDAC4 activity and its functions in inflammation, insulin signaling and glucose metabolism, and cardiac muscle development.

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease.

Vascular calcification is a major risk factor for cardiovascular disease mortality, with a significant prevalence in chronic kidney disease (CKD). Pharmacological inhibition of histone acetyltransferase has been proven to protect against from vascular calcification. However, the role of Histone Deacetylase 2 (HDAC2) and molecular mechanisms in vascular calcification of CKD remains unknown. An invivo model of CKD was established using mouse fed with a high adenine and phosphate diet, and an invitro model was produced using human aortic vascular smooth muscle cells (VSMCs) stimulated with β-glycerophosphate (β-GP). HDAC2 expression was found to be reduced in medial artery of CKD mice and β-GP-induced VSMCs. Overexpression of HDAC2 attenuated OPN and OCN upregulation, α-SMA and SM22α downregulation, and calcium deposition in aortas of CKD. The invitro results also demonstrated that β-GP-induced osteogenic differentiation was inhibited by HDAC2. Furthermore, we found that HDAC2 overexpression caused an increase in LC3II/I, a decrease in p62, and an induction of autophagic flux. Inhibition of autophagy using its specific inhibitor 3-MA blocked HDAC2's protective effect on osteogenic differentiation in β-GP-treated VSMCs. Taken together, these results suggest that HDAC2 may protect against vascular calcification by the activation of autophagy, laying out a novel insight for the molecular mechanism in vascular calcification of CKD.

Role of microRNAs deregulation in initiation of rheumatoid arthritis: A retrospective observational study.

Rheumatoid arthritis (RA) is a joint disorder and is considered an important public health concern nowadays. So, identifying novel biomarkers and treatment modalities is urgently needed to improve the health standard of RA patients. Factors involved in RA pathogenesis are genetic/epigenetic modification, environment, and lifestyle. In the case of epigenetic modification, the expression deregulation of microRNAs and the role of histone deacetylase (HDAC) in RA is an important aspect that needs to be addressed. The present study is designed to evaluate the expression pattern of microRNAs related to the HDAC family. Five microRNAs, miR-92a-3p, miR-455-3p, miR-222, miR-140, and miR-146a related to the HDAC family were selected for the present study. Real-time polymerase chain reaction was used to estimate the level of expression of the above-mentioned microRNAs in 150 patients of RA versus 150 controls. Oxidative stress level and histone deacetylation status were measured using the enzyme-linked immunosorbent assay. Statistical analysis showed significant downregulation (P < .0001) of selected microRNAs in RA patients versus controls. Significantly raised level of HDAC (P < .0001) and 8-hydroxy-2'-deoxyguanosine (P < .0001) was observed in patients versus controls. A good diagnostic potential of selected microRNAs in RA was shown by the receiver operating curve analysis. The current study showed a significant role of deregulated expression of the above-mentioned microRNAs in RA initiation and can act as an excellent diagnostic marker for this disease.

HDAC11 Regulates Palmitate-induced NLRP3 Inflammasome Activation by Inducing YAP Expression in THP-1 Cells and PBMCs.

Histone deacetylase 11 (HDAC11) has been implicated in the pathogenesis of metabolic diseases characterized by chronic low-grade inflammation, such as obesity. However, the influence of HDAC11 on inflammation and the specific effect of HDAC11 on the palmitic acid (PA)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation are poorly understood. The effect of PA treatment on HDAC11 activity and the NLRP3 inflammasome was investigated in human peripheral blood mononuclear cells and THP-1 cells. The PA-induced responses of key markers of NLRP3 inflammasome activation, including NLRP3 gene expression, caspase-1 p10 activation, cleaved IL-1β production, and extracellular IL-1β release, were assessed as well. The role of HDAC11 was explored using a specific inhibitor of HDAC11 and by knockdown using small interfering (si)HDAC11 RNA. The relationship between HDAC11 and yes-associated protein (YAP) in the PA-induced NLRP3 inflammasome was investigated in THP-1 cells with HDAC11 or YAP knockdown. Following PA treatment, HDAC11 activity and protein levels increased significantly, concomitant with activation of the NLRP3 inflammasome. Notably, PA-induced the upregulation of NLRP3, caspase-1 p10 activation, the production of cleaved IL-1β, and the release of IL-1β into the extracellular space, all of which were attenuated by FT895 treatment and by HDAC11 knockdown. In THP-1 cells, PA induced the expression of YAP and its interaction with NLRP3, resulting in NLRP3 inflammasome activation, whereas both were inhibited by FT895 and siHDAC11 RNA. These findings demonstrate a pivotal role for HDAC11 in the PA-induced activation of the NLRP3 inflammasome. HDAC11 inhibition thus represents a promising therapeutic strategy for mitigating NLRP3 inflammasome-related inflammation in the context of obesity.

Role of Histone Deacetylase 6 and Histone Deacetylase 6 Inhibition in Colorectal Cancer.

Histone deacetylase 6 (HDAC6), by deacetylation of multiple substrates and association with interacting proteins, regulates many physiological processes that are involved in cancer development and invasiveness such as cell proliferation, apoptosis, motility, epithelial to mesenchymal transition, and angiogenesis. Due to its ability to remove misfolded proteins, induce autophagy, and regulate unfolded protein response, HDAC6 plays a protective role in responses to stress and enables tumor cell survival. The scope of this review is to discuss the roles of HDCA6 and its implications for the therapy of colorectal cancer (CRC). As HDAC6 is overexpressed in CRC, correlates with poor disease prognosis, and is not essential for normal mammalian development, it represents a good therapeutic target. Selective inhibition of HDAC6 impairs growth and progression without inducing major adverse events in experimental animals. In CRC, HDAC6 inhibitors have shown the potential to reduce tumor progression and enhance the therapeutic effect of other drugs. As HDAC6 is involved in the regulation of immune responses, HDAC6 inhibitors have shown the potential to improve antitumor immunity by increasing the immunogenicity of tumor cells, augmenting immune cell activity, and alleviating immunosuppression in the tumor microenvironment. Therefore, HDAC6 inhibitors may represent promising candidates to improve the effect of and overcome resistance to immunotherapy.

The Roles of Histone Deacetylases in the Regulation of Ovarian Cancer Metastasis.

Ovarian cancer is the most lethal gynecologic malignancy, and metastasis is the major cause of death in patients with ovarian cancer, which is regulated by the coordinated interplay of genetic and epigenetic mechanisms. Histone deacetylases (HDACs) are enzymes that can catalyze the deacetylation of histone and some non-histone proteins and that are involved in the regulation of a variety of biological processes via the regulation of gene transcription and the functions of non-histone proteins such as transcription factors and enzymes. Aberrant expressions of HDACs are common in ovarian cancer. Many studies have found that HDACs are involved in regulating a variety of events associated with ovarian cancer metastasis, including cell migration, invasion, and the epithelial-mesenchymal transformation. Herein, we provide a brief overview of ovarian cancer metastasis and the dysregulated expression of HDACs in ovarian cancer. In addition, we discuss the roles of HDACs in the regulation of ovarian cancer metastasis. Finally, we discuss the development of compounds that target HDACs and highlight their importance in the future of ovarian cancer therapy.

HDAC6 and ERK/ADAM17 Regulate VEGF-Induced NOTCH Signaling in Lung Endothelial Cells.

Angiogenesis plays a critical role in various physiological and pathological processes and is regulated by VEGF. Histone Deacetylase 6 (HDAC6) is a class IIB HDAC that regulates cytoplasmic signaling through deacetylation and is emerging as a target for modulating angiogenesis. We investigated the hypothesis that VEGF-induced endothelial cell (EC) NOTCH signaling is regulated by HDAC6 through acetylation of NOTCH intracellular cytoplasmic domain (NICD). In pulmonary endothelial cells (EC), VEGF-induced activation of the NICD transcriptional response was regulated by ERK1/2 and ADAM 17 and required DLL4. While HDAC6 inhibition induced the acetylation of NICD and stabilized NICD, it repressed NICD-SNW1 binding required for the NOTCH transcriptional responses. In vitro experiments showed that HDAC6 inhibition inhibited lung EC angiogenesis, and neonatal mice treated with a systemic HDAC6 inhibitor had significantly altered angiogenesis and alveolarization. These findings shed light on the role of HDAC6 in modulating VEGF-induced angiogenesis through acetylation and repression of the transcriptional regulators, NICD and SNW1.

HDACs alters negatively to the tumor immune microenvironment in gynecologic cancers

The role of histone deacetylases (HDACs) in the tumor immune microenvironment of gynecologic tumors remains unexplored. We integrated data from The Cancer Genome Atlas and Human Protein Atlas to examine HDAC expression in breast, cervical, ovarian, and endometrial cancers. Elevated HDAC expression correlated with poor prognosis and highly malignant cancer subtypes. Gene Set Enrichment Analysis revealed positive associations between HDAC expression and tumor proliferation signature, while negative associations were found with tumor inflammation signature. Increased HDAC expression was linked to reduced infiltration of natural killer (NK), NKT, and CD8+ T cells, along with negative associations with the expression of PSMB10, NKG7, CCL5, CD27, HLA-DQA1, and HLA-DQB1. In a murine 4T1 breast cancer model, treatment with suberoylanilide hydroxamic acid (SAHA; HDAC inhibitor) and PD-1 antibody significantly inhibited tumor growth and infiltration of CD3+ and CD8+ T cells. Real-time polymerase chain reaction revealed upregulated expressions of Psmb10, Nkg7, Ccl5, Cd8a, Cxcr6, and Cxcl9 genes, while Ctnnb1 and Myc genes were inhibited, indicating tumor suppression and immune microenvironment activation. Our study revealed that HDACs play tumor-promoting and immunosuppressive roles in gynecologic cancers, suggesting HDAC inhibitors as potential therapeutic agents for these cancers.

Class I HDAC inhibitors attenuate dexamethasone-induced muscle atrophy via increased protein kinase C (PKC) delta phosphorylation

Skeletal muscle atrophy is defined by wasting or decrease in muscle mass owing to injury, aging, malnutrition, chronic disuse, or physical consequences of chronic illness. Under normal physiological conditions, a network of signal transduction pathways serves to balance muscle protein synthesis and proteolysis; however, metabolic shifts occur from protein synthesis to protein degradation that leads to a reduction in cross-sectional myofibers and can result in loss of skeletal muscle mass (atrophy) over time. Recent evidence highlights posttranslational modifications (PTMs) such as acetylation and phosphorylation in contractile dysfunction and muscle wasting.Indeed, histone deacetylase (HDAC) inhibitors have been shown to attenuate muscle atrophy and delay muscle damage in response to nutrient deprivation, in models of metabolic dysfunction and genetic models of muscle disease (e.g., muscle dystrophy). Despite our current understanding of lysine acetylation in muscle physiology, a role for HDACs in the regulation of muscle signal transduction remains a ‘black box.’ Using C2C12 myotubes stimulated with dexamethasone (Dex) as a model of muscle atrophy, we report that protein kinase C delta (PKCδ) phosphorylation decreased at threonine 505 (T505) and serine 643 (S643) in myotubes in response to muscle atrophy; these residues are important for PKCδ activity. Interestingly, PKCδ phosphorylation was restored/increased in myotubes treated with a pan-HDAC inhibitor or a class I selective HDAC inhibitor targeting HDACs1, −2, and − 3 in response to Dex. Moreover, we observed that Dex induced atrophy in skeletal muscle tissue in mice; this reduction in atrophy occurred rapidly, with weight loss noted by day 3 post-Dex and muscle weight loss noted by day 7. Similar to our findings in C2C12 myotubes, Dex attenuated phosphorylation of PKCδ at S643, while HDAC inhibition restored or increased PKCδ phosphorylation at both T505 and S643 in the tibialis anterior. Consistent with this hypothesis, we report that HDAC inhibition could not restore myotube size in response to Dex in the presence of a PKCδ inhibitor or when overexpressing a dominant negative PKCδ. Additionally, the overexpression of a constitutively active PKCδ prevented Dex-induced myotube atrophy. Combined, these data suggest that HDACs regulate muscle physiology via changes in intracellular signaling, namely PKCδ phosphorylation. Whether HDACs regulate PKCδ through canonical (e.g. gene-mediated regulation of phosphatases) or non-canonical (e.g. direct deacetylation of PKCδ to change phosphorylation states) mechanisms remain unclear and future research is needed to clarify this point.

Role of Histone Deacetylases in the Pathogenesis of Salivary Gland Tumors and Therapeutic Targeting Options.

Salivary gland tumors (SGTs) comprise a rare and heterogenous category of benign/malignant neoplasms with progressively increasing knowledge of the molecular mechanisms underpinning their pathogenesis, poor prognosis, and therapeutic treatment efficacy. Emerging data are pointing toward an interplay of genetic and epigenetic factors contributing to their heterogeneity and diverse clinical phenotypes. Post-translational histone modifications such as histone acetylation/deacetylation have been shown to actively participate in the pathobiology of SGTs, further suggesting that histone deacetylating factors (HDACs), selective or pan-HDAC inhibitors (HDACis), might present effective treatment options for these neoplasms. Herein, we describe the molecular and epigenetic mechanisms underlying the pathology of the different types of SGTs, focusing on histone acetylation/deacetylation effects on gene expression as well as the progress of HDACis in SGT therapy and the current status of relevant clinical trials.

Targeting histone deacetylases for cancer therapy: Trends and challenges.

Dysregulation of histone deacetylases (HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors (HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.