Single-Nucleus RNA Sequencing Reveals HDAC6 Inhibition Reverses Doxorubicin-Induced Cognitive Impairment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE271055 | GEO | 2025/06/26
REPOSITORIES: GEO
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Project description:Single-Nucleus RNA Sequencing Reveals HDAC6 Inhibition Reverses Doxorubicin-Induced Cognitive Impairment
| PRJNA1129505 | ENA
Project description:Breast cancer is the most common female malignancy in both the developed and developing world. Doxorubicin is one of the most commonly used chemotherapies for breast cancer. Unfortunately, up to 60% of survivors report long-term chemotherapy-induced cognitive dysfunction (CICD) characterized by deficits in working memory, processing speed and executive function. Currently, no therapeutic standard for treating CICD exists. Here, we hypothesized that treatment with a blood-brain barrier permeable histone deacetylase 6 (HDAC6) inhibitor can successfully reverse long-term doxorubicin-induced cognitive dysfunction. Methods: The puzzle box test and novel object/place recognition test were used to assess cognitive function following a therapeutic doxorubicin dosing schedule in female mice. Mitochondrial function and morphology in neuronal synaptosomes were evaluated using the Seahorse XF24 extracellular flux analyzer and transmission electron microscopy, respectively. Hippocampal postsynaptic integrity was evaluated using immunofluorescence. Hippocampal microglia phenotype was determined using advanced imaging techniques and single-nucleus RNA sequencing. Results: A 14-day treatment with a blood-brain barrier permeable HDAC6 inhibitor successfully reversed long-term CICD in the domains of executive function, working and spatial memory. No significant changes in mitochondrial function or morphology in neuronal synaptosomes were detected. Long-term CICD was associated with a decreased expression of postsynaptic PSD95 in the hippocampus. These changes were associated with decreased microglial ramification and alterations in the microglia transcriptome that suggest a stage 1 disease-associated microglia (DAM) phenotype. HDAC6 inhibition completely reversed these doxorubicin-induced alterations, indicating a restoration of microglial homeostasis. Conclusion: Our results show that decreased postsynaptic integrity and a neurodegenerative microglia phenotype closely resembling stage 1 DAM microglia contribute to long-term CICD. Moreover, HDAC6 inhibition shows promise as an efficacious pharmaceutical intervention to alleviate CICD and improve quality of life of breast cancer survivors.
| S-EPMC8692908 | biostudies-literature
Project description:Chemotherapy-induced cognitive impairment (CICI) is a commonly reported neurotoxic side effect of chemotherapy, occurring in up to 75% cancer patients. CICI manifests as decrements in working memory, executive functioning, attention, and processing speed, and greatly interferes with patients' daily performance and quality of life. Currently no treatment for CICI has been approved by the US Food and Drug Administration. We show here that treatment with a brain-penetrating histone deacetylase 6 (HDAC6) inhibitor for two weeks was sufficient to fully reverse cisplatin-induced cognitive impairments in male mice, as demonstrated in the Y-maze test of spontaneous alternation, the novel object/place recognition test, and the puzzle box test. Normalization of cognitive impairment was associated with reversal of cisplatin-induced synaptosomal mitochondrial deficits and restoration of synaptic integrity. Mechanistically, cisplatin induced deacetylation of the microtubule protein α-tubulin and hyperphosphorylation of the microtubule-associated protein tau. These cisplatin-induced changes were reversed by HDAC6 inhibition. Our data suggest that inhibition of HDAC6 restores microtubule stability and reverses tau phosphorylation, leading to normalization of synaptosomal mitochondrial function and synaptic integrity and thereby to reversal of CICI. Remarkably, our results indicate that short-term daily treatment with the HDAC6 inhibitor was sufficient to achieve prolonged reversal of established behavioral, structural and functional deficits induced by cisplatin. Because the beneficial effects of HDAC6 inhibitors as add-ons to cancer treatment have been demonstrated in clinical trials, selective targeting of HDAC6 with brain-penetrating inhibitors appears a promising therapeutic approach for reversing chemotherapy-induced neurotoxicity while enhancing tumor control.
| S-EPMC6166273 | biostudies-literature
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
2024-08-19 | GSE273645 | GEO
Project description:Histone deacetylases (HDACs) are crucial regulators of gene expression, DNA synthesis, and cellular processes, making them essential targets in cancer research. HDAC6, specifically, influences protein stability and chromatin dynamics. Despite HDAC6's potential therapeutic value, its exact role in gene regulation and chromatin remodeling needs further clarification. This study examines how HDAC6 inactivation influences lysine acetyltransferase P300 stabilization and subsequent effects on chromatin structure and function in cancer cells. We employed the HDAC6 inhibitor ITF3756, siRNA, or CRISPR/Cas9 gene editing to inactivate HDAC6 in different epigenomic backgrounds. Constantly, this inactivation led to significant changes in chromatin accessibility, particularly increased acetylation of histone H3 lysines 9, 14, and 27 (ATAC-seq and H3K27Ac ChIP-seq analysis). Transcriptomics, proteomics, and gene ontology analysis revealed gene changes in cell proliferation, adhesion, migration, and apoptosis. Significantly, HDAC6 inactivation altered P300 ubiquitination, stabilizing P300 and leading to downregulating genes critical for cancer cell survival. Our study highlights the substantial impact of HDAC6 inactivation on the chromatin landscape of cancer cells and suggests a role for P300 in contributing to the anticancer effects. The stabilization of P300 with HDAC6 inhibition proposes a potential shift in therapeutic focus from HDAC6 itself to its interaction with P300. This finding opens new avenues for developing targeted cancer therapies, improving our understanding of epigenetic mechanisms in cancer cells.
2024-08-19 | GSE273644 | GEO
Project description:Heart failure with preserved ejection fraction (HFpEF) is a prevalent health condition associated with high morbidity and mortality, but currently, there are few effective therapies. Our previous research showed that inhibiting histone deacetylase 6 (HDAC6) had a beneficial effect on a genetic cardiomyopathy model. The overlapping underlying mechanisms involving inflammation and metabolism between cardiomyopathy and HFpEF prompted us to explore the role of HDAC6 in HFpEF. The results showed that inhibiting HDAC6 with TYA-018 reversed preexisting cardiac hypertrophy and diastolic dysfunction, and improved lung congestion and exercise capacity in mouse models of HFpEF, including a newly developed model that combines moderate trans-aortic constriction and high-fat diet to mimic the systemic and cardiovascular features of human HFpEF. Moreover, mice with genetic Hdac6 deletion delayed the development of HFpEF and were resistant to the effects of TYA-018. The efficacy of TYA-018 was comparable to a SGLT2 inhibitor, and the combination showed increased effects. Mechanistically, TYA-018 restored expression of gene sets associated with hypertrophy, fibrosis, and mitochondrial energy production in heart tissue from HFpEF mice. TYA-018 also inhibited activation of human cardiac fibroblasts and increased mitochondrial respiratory capacity in induced pluripotent stem cell–derived cardiomyocytes. These findings support the direct role of HDAC6 on HFpEF pathophysiology in the heart and that inhibiting HDAC6 may be a promising approach to treating HFpEF.
2024-01-18 | GSE249412 | GEO
Project description:Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.
| S-EPMC5435512 | biostudies-literature
Project description:Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. RNase T2 upregulation upon HDAC6 loss was restricted to myeloid but not B-ALL cells. Pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting both ex vivo and in vivo demonstrated that HDAC6 inhibition sensitized murine AML cells to broad CD8+ T cell activation as evidenced by increased TNFα and CD107a expression. Consistently, in a syngeneic AML model, HDAC6 inhibition restricted AML cell growth. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor Ricolinostat in AML cell lines or pediatric patient derived PDX-AML cells, while showing limited synergy in ALL cell lines, PDX-ALL cells or healthy controls. These findings establish HDAC6 inhibition as a dual-modality therapeutic strategy in myeloid leukemia, enhancing both immune activation and chemosensitivity.
2025-05-23 | GSE297366 | GEO
Project description:Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. RNase T2 upregulation upon HDAC6 loss was restricted to myeloid but not B-ALL cells. Pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting both ex vivo and in vivo demonstrated that HDAC6 inhibition sensitized murine AML cells to broad CD8+ T cell activation as evidenced by increased TNFα and CD107a expression. Consistently, in a syngeneic AML model, HDAC6 inhibition restricted AML cell growth. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor Ricolinostat in AML cell lines or pediatric patient derived PDX-AML cells, while showing limited synergy in ALL cell lines, PDX-ALL cells or healthy controls. These findings establish HDAC6 inhibition as a dual-modality therapeutic strategy in myeloid leukemia, enhancing both immune activation and chemosensitivity.
2025-05-23 | GSE297364 | GEO
Project description:Histone deacetylase 6 (HDAC6) is overexpressed in multiple myeloma (MM) patients and may be involved in the acquisition of resistance to conventional treatments. Here, we propose a two-residue mutation impairing the HDAC6 ZnF-UBP domain. HDAC6 knockout and ZnF-UBP mutant RPMI 8226 MM cell lines were generated using CRISPR-Cas9. MM cells harboring this mutation showed impaired aggresome formation, cell growth and a dysregulated gene expression profile in a more pronounced manner than the HDAC6 knockout cells.
2024-04-08 | GSE263138 | GEO