Project description:To investigate whether microRNAs (miRNAs) were induced by histone deacetylase inhibitors (HDACi) in human gastric cancer cells, the miRNA-seq was used to screen differentially expressed miRNAs in two human gastric cancer cell lines (HGC-27 and AGS) treated with the HDACi vorinostat (SAHA) or vehicle (DMSO).
Project description:The identification of proteins that change in response to a drug perturbation can shed light on the molecular mechanisms of the drug and its potential use in therapies. Histone deacetylases (HDACs) are targets for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is an FDA approved HDAC inhibitor used for the treatment of cutaneous T-cell lymphoma. ING2 is a non-catalytic component of the Sin3/HDAC complex. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. We then assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2's association with the complex. Cells from human breast cancer cell line MDA-MB-231 were treated with the HDAC inhibitor drug SAHA in duplicate and compared to a DMSO vehicle control in triplicate, for a total of 5 samples.
Project description:The identification of proteins that change in response to a drug perturbation can shed light on the molecular mechanisms of the drug and its potential use in therapies. Histone deacetylases (HDACs) are targets for cancer therapy. Suberoylanilide hydroxamic acid (SAHA) is an FDA approved HDAC inhibitor used for the treatment of cutaneous T-cell lymphoma. ING2 is a non-catalytic component of the Sin3/HDAC complex. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. We then assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2's association with the complex.
Project description:The Sin3/HDAC multi-protein complex consists of at least 17 subunits and is known to have roles in diverse biological and cellular processes including transcription, chromatin structure, and the cell cycle. ING2 is a non-catalytic component of this complex. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. Suberoylanilide hydroxamic acid (SAHA) is an FDA approved HDAC inhibitor used for the treatment of cutaneous T-cell lymphoma. We assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2âs association with the complex. ING2 siRNA knockdowns in human breast cancer cell line MDA-MB-231 were compared to a non-targeting control in triplicate, for a total of 6 samples.
Project description:Analysis of HeLa cells treated with histone deacetylase inhibitor SAHA for 24hr. Results provide insight into the effect of SAHA on the activation of lysosomal and autophagy pathways
Project description:Co-targeting the plasticity and heterogeneity of cancer is fundamental to achieve and maintain complete remission (CR). We exploited murine models of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia driven by the promyelocytic leukemia/retinoic acid receptor (PML-RARα) oncofusion protein, which recruits histone deacetylase (HDAC)-containing complexes. We investigated the effect of two HDAC inhibitors: valproic acid (VPA), and SAHA/vorinostat with all-trans retinoic acid (ATRA), on the bulk cells and LICs of two APLs with different LIC frequencies. VPA and SAHA selectively target the bulk APL cells and LICs respectively. VPA+SAHA+ATRA combination induced CR in an APL model with lower LIC frequency.
Project description:Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, mitosis and cytokinesis were inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. Chromatin-immunoprecipitation-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. Collectively, our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy. ChIP-chip analysis for H3K9K14ac in A549, H1299 and CL1-1 lung cancer cells treated with 2.5 uM histone deacetylase inhibitor, OSU-HDAC-44, for 2 hours.
Project description:Analysis of gene expression change after 8hr's treatment with 5μM SAHA, which is a histone deacetylase inhibitor, in MDA-MB-231 cell lines.
Project description:The Sin3/HDAC multi-protein complex consists of at least 17 subunits and is known to have roles in diverse biological and cellular processes including transcription, chromatin structure, and the cell cycle. ING2 is a non-catalytic component of this complex. To obtain a better mechanistic understanding of the Sin3/HDAC complex in cancer, we extended its protein-protein interaction network and identified a mutually exclusive pair within the complex. Suberoylanilide hydroxamic acid (SAHA) is an FDA approved HDAC inhibitor used for the treatment of cutaneous T-cell lymphoma. We assessed the effects of SAHA on the disruption of the complex network through six homologous baits. SAHA perturbs multiple protein interactions and therefore compromises the composition of large parts of the Sin3/HDAC network. A comparison of the effect of SAHA treatment on gene expression in breast cancer cells to a knockdown of the ING2 subunit indicated that a portion of the anticancer effects of SAHA may be attributed to the disruption of ING2’s association with the complex.
Project description:The human stool samples were collected and processed for in vitro culturing under anaerobic condition using rapidAIM assay with or without SAHA, an lysine deacetylase inhibitor, for evaluating the effects of SAHA on human gut microbiome. Metaproteomics were used to analyze the microbiome composition and functions.