Structural diversification and selective inhibition of HDAC3: A comprehensive review of inhibitors and degraders.

Lithium is an effective mood stabilizer that has been clinically used to treat bipolar disorder for several decades. Recent studies have suggested that lithium possesses robust neuroprotective and anti-tumor properties. Thus far, a large number of lithium targets have been discovered. Here, we report for the first time that HDAC1 is a target of lithium. Lithium significantly down-regulated HDAC1 at the translational level by targeting HDAC1 mRNA. We also showed that depletion of HDAC1 is essential for the neuroprotective effects of lithium and for the lithium-mediated degradation of mutant huntingtin through the autophagic pathway. Our studies explain the multiple functions of lithium and reveal a novel mechanism for the function of lithium in neurodegeneration.

Multiple myeloma (MM) is one of the many types of hematological malignancies, and many novel drugs, including histone deacetylase (HDAC) inhibitors such as panobinostat (pan-HDAC), romidepsin (HDAC1-3-specific), ACY-1215 and ACY-241 (HDAC6-specific) are currently undergoing preclinical and clinical evaluation.Daratumumab, an anti-CD38 monoclonal antibody, is a promising agent showing high activity in relapsed/refractory MM. However, some patients become resistant to daratumumab, partly due to the reduced CD38 expression in MM cells. It was previously shown that panobinostat increased CD38 expression in a time-dependent manner, particularly after 72 h (García et al). In our study, treatment with panobinostat for 24 h did not change the expression of CD38. Moreover, the expression of MHC class I chain-related gene A (MICA) was increased by all the examined HDAC inhibitors following treatment for 24 h (Figure 1). We established luciferase-expressing MM cell lines and examined antibody-dependent cell-mediated cytotoxicity (ADCC) in a luciferase assay. ADCC was enhanced after 24 h-treatment with the examined HDAC inhibitors (Figure 2). These results suggest that induction of MICA plays an important role in the enhancement of ADCC by HDAC inhibitors.Furthermore, HDAC inhibitors decreased the expression of CD55 and CD59. Presumably, CD55 and CD59 inhibit complement activation and suppress complement-dependent cytotoxicity (CDC). We found the possibility of CDC enhancement of daratumumab by HDAC inhibitors in the luciferase assay.CD47 in tumor cells inhibits phagocytosis. Blockade of interaction between CD47 in tumor cells and signal regulatory protein α (SIRP-α) in macrophages increases tumor cell phagocytosis in hematological malignancies. Moreover, the treatment of MM cells with HDAC inhibitors decreased CD47 expression. Thus, the possibility of enhancement of antibody-dependent cellular phagocytosis (ADCP) by daratumumab in these cells was suggested.Ikaros family zinc finger 1 (IKZF1) is a transcription factor and pivotal target of immunomodulatory drugs (IMiDs). IMiDs mediate the binding of IKZF1 to cereblon complex and degrades IKZF1, thereby causing the loss of interferon regulatory factor 4 and MYC expression. A previous report showed that IKZF1 could suppress the transcription of MICA (Fionda et al). Here, we found that MM cells treated with HDAC inhibitors showed downregulated expression of IKZF1 mRNA (Figure 3). These results suggest the possibility that HDAC inhibitors increase MICA expression via inhibition of IKZF1, its negative regulator. IKZF1 could be a novel target of HDAC inhibitors, including panobinostat, romidepsin, ACY-1215 and ACY-241. Furthermore, it was presumed that IKZF1 is suppressed by HDAC inhibitors in a cereblon-independent manner.Afuresertib is an oral AKT inhibitor, which has been clinically tested in patients with advanced hematological malignancies. Single-agent afuresertib showed a favorable safety profile and demonstrated clinical activity against patients with MM in phase I of a clinical trial (Spencer et al). In a proliferation assay, we found that afuresertib combined with HDAC inhibitors showed higher cytotoxicity than that of each agent used singly (Figure 4). The expression of cleaved caspase 3 and caspase 7 was induced more in MM cells treated with a combination of HDAC and AKT inhibitors than in those treated with only one agent. These results suggested that the combination of HDAC and AKT inhibitors strongly induces the apoptosis of MM cells. Moreover, the addition of AKT inhibitors to HDAC inhibitors caused a decrease in CD55, CD59 and CD47 expression.The findings of the present study suggest the possibility that combination therapy with HDAC and AKT inhibitors could overcome drug resistance via multiple action mechanisms. Firstly, HDAC inhibitors could enhance ADCC owing to increased MICA expression, and these may be effective in patients with reduced CD38 expression during daratumumab therapy. Secondly, the possibility of IKZF1 decrease by HDAC inhibitors in a cereblon-independent manner was presumed. Thirdly, a combination of HDAC and AKT inhibitors induced strong apoptosis in MM cells, and it may enhance the CDC and ADCP of daratumumab. These data suggest that the addition of HDAC and AKT inhibitors to daratumumab could be an effective therapy for relapsed/refractory MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Loss of primary cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose primary cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores primary cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of primary cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of primary cilium formation in PDAC cells.

The prefrontal cortex (PFC), a region responsible for high-order cognitive functions, such as decision-making, attention and working memory, is highly influenced by stress and corticosteroid stress hormones. Recently it has been shown that acute stress affects PFC functions by potentiating glutamatergic transmission via a mechanism dependent on glucocorticoid receptor (GR) and its downstream target, serum and glucocorticoid-inducible kinase (SGK). To identify the key regulators of stress responses, we examined the role of histone deacetylase 6 (HDAC6), a unique member of the HDAC family that could regulate the GR chaperone protein heat shock protein 90 (HSP90), in the synaptic action of acute stress in PFC. We found that HDAC6 inhibition or knockdown blocked the enhancement of glutamatergic transmission and glutamate receptor trafficking by acute stress in vivo or corticosterone treatment in vitro. In addition, HDAC6 inhibition blocked the up-regulation of SGK in animals exposed to acute stress. HSP90 inhibition or knockdown produced a similar blockade of the acute stress-induced enhancement of glutamatergic signalling. These findings have identified HDAC6 as a key molecule gating the effects of acute stress on synaptic functions in the PFC.

Histone deacetylase 9 (HDAC9), like most Class II HDACs, catalyzes the removal of acetyl moieties from the ε-amino groups of conserved lysine residues in the N-terminal tail of histones. Biologically, HDAC9 regulates a wide variety of normal and abnormal physiological functions, including cardiac growth, T-regulatory cell function, neuronal disorders, muscle differentiation, development, and cancer. In a biochemical approach to identify non-histone substrates of HDAC9, we found that HDAC9 co-purifies specifically with the ataxia telangiectasia group D-complementing (ATDC; also called TRIM29) protein. HDAC9 deacetylates ATDC, alters the ability of ATDC to associate with p53, and consequently inhibits the cell proliferation-promoting activity of ATDC. These results implicate the importance of non-histone deacetylation by HDAC9 and confirm and further extend the multifunctions of this Class II deacetylase.

Colon cancer is one of the most prevalent malignancies of the digestive system, characterized by high morbidity and mortality rates. Its development is driven by a complex interplay of factors within cancer cells and the tumor microenvironment (TME). Microsatellite-stable (MSS) colorectal cancer, often referred to as a “cold tumor, ” is characterized by chromosomal stability and a lack of neoantigen production. As a result, MSS tumors are generally unresponsive to immunotherapy. Post-translational modifications of proteins are critical in tumor remodeling and progression. Histone deacetylase 6 (HDAC6), a member of the HDAC family, plays a key role in regulating the deacetylation of both histone and non-histone substrates. Overexpression of HDAC6 has been reported in multiple tumor types and is associated with tumor growth and metastasis. While immune checkpoint blockade (ICB) therapies, such as those targeting programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand 1 (PD-L1), have achieved clinical success in several malignancies, the majority of colorectal cancer patients particularly those with MSS tumors fail to respond to these treatments. Recent evidence indicates that the intratumoral immune context strongly influences the efficacy of ICB therapies. Patients with high levels of intratumoral CD8+ T cell infiltration, elevated tumor mutational burden (TMB), and increased PD-L1 expression within the TME are more likely to respond favorably to immunotherapy. In this study, we focused on enhancing the immunogenicity of the TME and upregulating PD-L1 expression through selective HDAC6 inhibition to improve the efficacy of anti-PD-L1 immunotherapy. Analysis of The Cancer Genome Atlas (TCGA) data revealed that HDAC6 expression is inversely correlated with several immune-related genes, including PD-L1. This inverse relationship suggests a potential role for HDAC6 in regulating immune responses in MSS colorectal cancer. These findings imply that HDAC6 may influence the TME and immune evasion mechanisms, particularly by modulating immune checkpoint molecules such as PD-L1. In the CT26 syngeneic mouse model, inhibition of HDAC6 led to an enhanced immune response characterized by increased PD-L1 expression, improved antigen presentation, and upregulation of MHC-II. This was accompanied by a polarization toward M1 macrophages and elevated levels of pro-inflammatory cytokines, including TNF-α and IFN-γ, which are crucial for T cell activation. Furthermore, HDAC6 inhibition resulted in a reduction of TGF-β, a key immunosuppressive cytokine, thereby moderating immune suppression within the tumor microenvironment. These results highlight the potential of HDAC6 inhibitors to reprogram the tumor immune landscape and sensitize MSS colorectal cancer to immune checkpoint therapies. Citation Format: Ahran Yu, Jeong Eun Kang, Ju Yeon Park, Seijong Kim, Hye Kyung Hong, Yong Beom Chov. Targeting HDAC6 to modulate the tumor microenvironment and enhance anti-PD-L1 immunotherapy in MSS colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2168.

HDAC Class I Inhibition Acetylates a Non-Histone Protein STAT3 by Modulating p300-STAT3-HDAC1 Interaction In Activated B- Cell Like (ABC) Diffuse Large B Cell Lymphoma

Multiple myeloma (MM) is a neoplastic proliferation of plasma cells and remains an incurable disease because of the development of drug resistance. Histone deacytylase (HDAC) inhibitors are a new class of chemotherapeutic reagents that cause growth arrest and apoptosis of neoplastic cells. Depsipeptide, a new member of the HDAC inhibitors, was found to be safe in humans and has been shown to induce apoptosis in various cancers. In order to evaluate the effects of depsipeptide, a MM cell line, U266 [interleukin (IL)-6 dependent], was analysed for viability and apoptosis. The combined effect of depsipeptide with melphalan and changes in BCL-2 family proteins (BCL-2, BCL-XL, BAX and MCL-1) were also investigated. In addition, the RPMI 8226 cell line (IL-6 independent), and primary patient myeloma cells were also analysed for apoptosis after depsipeptide treatment. Depsipeptide induced apoptosis in both U266 and RPMI 8226 cell lines in a time- and dose-dependent fashion, and in primary patient myeloma cells. We also demonstrated that depsipeptide had an additive effect with melphalan (10 micromol/l). BCL-2, BCL-XL and MCL-1 showed decreased expression in depsipeptide-treated samples. Based on recent clinical trials demonstrating minimal clinical toxicity, our study supports the future clinical utilization of depsipeptide in the management of MM.

It is well known that atherosclerosis and restenosis are common cardiovascular diseases and major health care problems. Vascular remodeling and migration and proliferation of vascular smooth muscle cells (VSMCs) are key features of these pathologies. There has been enormous progress in drug development and clinical management of these disorders, with angioplasty and drug eluting stents being standard procedures to treat vascular obstruction. However, despite their benefits, these current treatment modalities are not always efficacious. Furthermore, they can also be associated with postoperative complications and graft failures, some of which can be life threatening. Evaluation of newer mechanisms involved in VSMC proliferation aimed at uncovering additional therapeutic approaches to curb VSMC dysfunction in cardiovascular diseases is clearly warranted. See accompanying article on page 851 Accumulating evidence suggests that several common diseases, including cardiovascular disorders, diabetes, and the vascular complications of diabetes, are governed by a combination of genetic and environmental factors and that epigenetic mechanisms, such as DNA methylation and histone modifications in chromatin, form a key link between them.1–3 Epigenetics is the added layer of gene regulation that occurs in chromatin without changes in the actual underlying DNA sequence and plays a major role in dictating cell-specific gene expression patterns and transcriptional outcomes.4,5 Along with DNA methylation, key posttranslational modifications of histone N-terminal tails can alter chromatin structure to form an added layer of gene regulation and modulate gene transcription.5 Therefore, gene transcription depends on chromatin structure, which is very dynamic, depending on a multitude of histone posttranslational modifications that allow for the conversion of inaccessible, compact, or …

Addition of Histone Deacetylase Inhibitors in Combination Therapy

The role and potential therapeutic application of HDAC6 inhibitors in inflammation-related diseases: A medicinal chemistry perspective.

Survivin is an oncogenic protein that is highly expressed in breast cancer and has a dual function that is dependent on its subcellular localization. In the cytosol, survivin blocks programmed cell death by inactivating caspase proteins; however, in the nucleus it facilitates cell division by regulating chromosomal movement and cytokinesis. In prior work, we showed that survivin is acetylated by CREB-binding protein (CBP), which restricts its localization to the nuclear compartment and thereby inhibits its anti-apoptotic function. Here, we identify histone deacetylase 6 (HDAC6) as responsible for abrogating CBP-mediated survivin acetylation in the estrogen receptor (ER)-positive breast cancer cell line, MCF-7. HDAC6 directly binds survivin, an interaction that is enhanced by CBP. In quiescent breast cancer cells in culture and in malignant tissue sections from ER+ breast tumors, HDAC6 localizes to a perinuclear region of the cell, undergoing transport to the nucleus following CBP activation where it then deacetylates survivin. Genetically modified mouse embryonic fibroblasts that lack mhdac6 localize survivin predominantly to the nuclear compartment, whereas wild-type mouse embryonic fibroblasts localize survivin to distinct cytoplasmic structures. Together, these data imply that HDAC6 deacetylates survivin to regulate its nuclear export, a feature that may provide a novel target for patients with ER+ breast cancer.

Histone Deacetylase 6 (HDAC6) is an intriguing therapeutic target in cancer research, distinguished as the only HDAC family member predominantly located in the cytoplasm. HDAC6 features two catalytic domains and a unique ubiquitin-binding domain, which sets it apart from other HDACs. Beyond its role in histone deacetylation, HDAC6 targets various nonhistone substrates, such as α-tubulin, cortactin, Heat Shock Protein 90 (HSP90), and Heat Shock Factor 1 (HSF1). Its involvement spans critical aspects of tumor progression, including invasion, metastasis, angiogenesis, drug resistance, stemness, and the reduction of tumor cell immunogenicity. Given these functions, HDAC6 inhibitors are emerging as valuable tools in the treatment of both solid and hematological tumors. Recent advancements have seen several HDAC6 inhibitors to enter clinical trials, with promising outcomes reported. This review covers the structural features of HDAC6, its biological roles, and its impact on tumor development, particularly focusing on progression-related events. Additionally, a detailed discussion of preclinical and clinical trials involving selective HDAC6 inhibitors is provided.

Cyclooxygenase-2 (COX-2) is considered to be a target for anticancer therapy. Histone deacetylase (HDAC) inhibitors exhibit antitumor activity, but the mechanisms of action are incompletely understood. We investigated whether HDAC inhibitors blocked AP-1-mediated activation of COX-2 transcription. Trichostatin A and suberoylanilide hydroxamic acid, two structurally related inhibitors of HDAC activity, blocked AP-1-mediated induction of COX-2 expression and prostaglandin E2 biosynthesis. Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c-Jun binding to the COX-2 promoter and thereby blocked transcription. The observed reduction in binding reflected reduced levels of c-Jun. HDAC inhibitors suppressed the induction of c-jun transcription by blocking the recruitment of the preinitiation complex (RNA polymerase II and TFIIB) to the c-jun promoter. HDAC3 but not HDAC1 or HDAC2 was required for AP-1-mediated stimulation of c-jun expression. Because HDAC inhibitors suppressed the induction of c-jun gene expression, resulting in reduced COX-2 transcription, it was important to determine whether other known AP-1 target genes were also modulated. Cyclin D1 and collagenase-1 are AP-1-dependent genes that have been implicated in carcinogenesis. HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase-1 transcription by inhibiting the binding of c-Jun to the respective promoters. Taken together, these results suggest that HDAC inhibitors block the induction of c-jun transcription by inhibiting the recruitment of the preinitiation complex to the c-jun promoter. This led, in turn, to reduced expression of several activator protein-1-dependent genes (COX-2, cyclin D1, collagenase-1). These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors.

The second coming of epigenetic drugs: a more strategic and broader research framework could boost the development of new drugs to modify epigenetic factors and gene expression.