HDAC6-Activatable Multifunctional Near-Infrared Probe for Glioma Cell Detection and Elimination.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor associated with limited treatment options and high drug resistance, presenting significant challenges in the pursuit of effective treatment strategies. Epigenetic modifications have emerged as promising diagnostic biomarkers and therapeutic targets for GBM. For instance, histone deacetylase 6 (HDAC6) has been identified as a potential pharmacological target for GBM. Furthermore, the overexpression of monoamine oxidase A (MAO A) in glioma has been linked to tumor progression, making it an attractive target for therapy. In this study, we successfully engineered HDAC-MB, an activatable multifunctional small-molecule probe with the goal of efficiently detecting and killing glioma cells. HDAC-MB can be selectively activated by HDAC6, leading to the "turn on" of near-infrared fluorescence and effective inhibition of MAO A, along with potent photodynamic therapy (PDT) effects. Consequently, HDAC-MB not only enables the imaging of HDAC6 in live glioma cells but also exhibits the synergistic effect of MAO A inhibition and PDT, effectively inhibiting glioma invasion and inducing cellular apoptosis. The distinctive combination of features displayed by HDAC-MB positions it as a versatile and highly effective tool for the accurate diagnosis and treatment of glioma cells. This opens up opportunities to enhance therapy outcomes and explore future applications in glioma theranostics.

Histone deacetylase 6: at the interface of cancer and neurodegeneration.

With the recognition in the early 1960s that histones can be post-translationally modified, the list of different post-translational modifications of histones and their biological consequences has continued to expand. In addition, the idea of the 'histone code' hypothesis, later introduced by David Allis and colleagues, further broaden the horizon of chromatin biology. Currently, there is a wealth of knowledge about the transition between the active and the repressive state of chromatin, and modifications of histones remains at the center of chromatin biology. Histone deacetylases (HDACs) in particular are of great importance for the therapeutic success of cancer treatment. Focusing primarily on HDAC6, herein we have briefly highlighted its unique involvement in cancer and also apparently in neurodegeneration.

Cancer (uncontrolled cell proliferation) and neurodegenerative diseases (loss of neurons/protein aggregation) are two distinct pathological conditions that share/overlap certain molecular determinants. Histone deacetylase 6 appears to be one such determinant for which researchers have made significant progress by accumulating sufficient evidence for its clinical translation in these aforementioned disease conditions.

Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC.

INTRODUCTION: In KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. METHODS: Using cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. RESULTS: Surprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. CONCLUSIONS: Exploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

Novel Histone Deacetylase 6 Inhibitor Confers Anti-inflammatory Effects and Enhances Gut Barrier Function.

Background/Aims: The purpose of the current study was to examine the anti-inflammatory effects of CKD-506, a novel histone deacetylase 6 inhibitor, on human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells and to explore the relationship between CKD-506 and gut epithelial barrier function. Methods: Lipopolysaccharide-stimulated human PBMCs from inflammatory bowel disease (IBD) patients were treated with CKD-506, and tumor necrosis factor (TNF)-α expression was measured using an enzyme-linked immunosorbent assay. The proliferation of CD4+ T cells from IBD patients was evaluated using flow cytometric analysis. The effects of CKD-506 on gut barrier function in a cell line and colon organoids, based on examinations of mRNA production, goblet cell differentiation, and E-cadherin recovery, were investigated using quantitative reverse transcription polymerase chain reaction, immunofluorescence, and a fluorescein isothiocyanate-dextran permeability assay. Results: Secretion of TNF-α, a pivotal pro-inflammatory mediator in IBD, by lipopolysaccharide-triggered PBMCs was markedly decreased by CKD-506 treatment in a dose-dependent manner and to a greater extent than by tofacitinib or tubastatin A treatment. E-cadherin mRNA expression and goblet cell differentiation increased significantly and dose-dependently in HT-29 cells in response to CKD-506, and inhibition of E-cadherin loss after TNF-α stimulation was significantly reduced both in HT-29 cells and gut organoids. Caco-2 cells treated with CKD-506 showed a significant reduction in barrier permeability in a dose-dependent manner. Conclusions: The present study demonstrated that CKD-506 has anti-inflammatory effects on PBMCs and CD4 T cells and improves gut barrier function, suggesting its potential as a small-molecule therapeutic option for IBD.

ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells.

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.

HDAC6 Inhibition Protects against OGDR-Induced Golgi Fragmentation and Apoptosis.

The Golgi apparatus (GA) is a pivotal organelle, and its fragmentation is an essential process in the development of apoptosis. GA is a potential target in the treatment of cerebral ischemia-reperfusion injury. Histone deacetylase 6 (HDAC6) catalyzes the removal of functional acetyl groups from proteins and plays an important role in cell homeostasis. In this study, the neuroprotective effects and the underlying mechanisms of HDAC6 inhibition were assessed in an ischemia-reperfusion injury model. Mouse neuroblastoma N2a cells and cultured neurons were subjected to oxygen-glucose deprivation/reperfusion (OGDR) insult. OGDR induces Golgi fragmentation and reduces tubulin acetylation in N2a cells and cultured neurons. Golgi fragmentation is prior to nuclear chromatin condensation after OGDR injury. Overexpression of GBF1 not only protects against OGDR-induced Golgi fragmentation but also protects against OGDR-induced apoptosis, suggesting that Golgi fragmentation is not secondary to apoptosis but plays a causal role for subsequent apoptosis. HDAC6 inhibition suppresses OGDR-induced tubulin deacetylation, p115 cleavage, and caspase 3 activation and protects against OGDR-induced Golgi fragmentation and apoptosis. This work opens a new avenue for potential clinical application of HDAC6 inhibitors for cerebral ischemia-reperfusion-related disorders.

Histone deacetylase 6 in cancer.

Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.