Project description:We have utilized a HDAC class-I specific inhbitor 4SC-202 and revealed a potential involvement of BRD4 and MYC in regulating the expression of induced genes in response to 4SC-202 treatment.
Project description:Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma
Project description:Unlike class I Histone deacetylase (HDAC) members (HDAC1, 2, 3, etc.), HDAC5, a class IIa HDAC member, is downregulated in multiple solid tumors, including pancreatic cancer, and its loss is associated with unfavorable prognosis. Additionally, HDAC5’s expression correlates negatively with arachidonic acid (AA) metabolism, which is highly implicated in inflammatory responses and cancer progression. This study aimed to elucidate the role of HDAC5 in AA metabolism and its prospect in the treatment of pancreatic cancer.
Project description:Histone deacetylases (HDAC) enzymes are chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic b cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic b-cell identity and function using trichostatin A (TSA), a pan-HDAC inhibitor. We observed that TSA alters insulin secretion associated with b-cell specific transcriptome programming in both mouse and human b-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative b-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
Project description:Histone deacetylases (HDAC) enzymes are chromatin modifiers which directly regulate gene expression through deacetylation of lysine residues within specific histone and non-histone proteins. A cell-specific gene expression pattern defines the identity of insulin-producing pancreatic b cells, yet molecular networks driving this transcriptional specificity are not fully understood. Here, we investigated the HDAC-dependent molecular mechanisms controlling pancreatic b-cell identity and function using trichostatin A (TSA), a pan-HDAC inhibitor. We observed that TSA alters insulin secretion associated with b-cell specific transcriptome programming in both mouse and human b-cell lines, as well as on human pancreatic islets. We also demonstrated that this alternative b-cell transcriptional program in response to HDAC inhibition is related to an epigenome-wide remodeling at both promoters and enhancers. Our data indicate that full HDAC activity is required to safeguard the epigenome, to protect against loss of β-cell identity with unsuitable expression of genes associated with alternative cell fates.
Project description:Project description: Taking advantage of a newly generated model system, we examined the influence of class I HDAC catalytic and non-catalytic function on the cellular proteome and acetylome. Therefore, we generated HAP1 cell lines either lacking individual class I HDACs or expressing catalytically inactive isoforms. Using these cell lines, we investigated whether deletion or inactivation of specific class I HDACs better mimics inhibitor treated cells using isobaric labeling (TMTpro).
Project description:Ten-to-Eleven Translocation (TET) family of proteins oxidize 5mC in to 5hmC on the genomic DNA and act as interesting class of epigenetic medulators. A novel small molecule inhbitor of TET enzymatic activity, C35 is developed.
