Inhibition of class I histone deacetylases 1 and 2 promotes urothelial carcinoma cell death by various mechanisms (HDAC siRNA knockdown)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE74477 | GEO | 2016/01/31
SECONDARY ACCESSION(S): PRJNA300533
REPOSITORIES: GEO
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Project description:Preliminary manuscript abstract: Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma (UC). To evaluate whether specific inhibition of HDAC1 and HDAC2 might serve as an appropriate therapy of UC we applied specific pharmacological inhibition of HDAC1 and HDAC2 with the two selective class I HDAC inhibitors Romidepsin and Givinostat. Treatment with the pan HDAC inhibitor SAHA served as an additional control. Romidepsin and Givinostat significantly reduced proliferation and clonogenicity of UC cells with minor effects on non-tumorigenic cells. Furthermore, compounds induced primarily S-phase disturbances and non-apoptotic cell death. Results of microarray analysis of HDAC inhibitor treated cells match with observed phenotype after pharmacological HDAC1 and HDAC2 inhibition in UC cells.
2016-01-31 | GSE70120 | GEO
Project description:Aberrant expression of histone deacetylases (HDACs) and their activity are associated with a broad range of tumor development. However, based on cell or tissue types, class IIA HDACs such as HDAC4 and HDAC5 may facilitate or inhibit cancer progression. The goal of this project is to examine the overall proteome changes caused by HDAC5 expression. Here, we studied the effects of stable expression of HDAC5 (that is normally downregulated or have a weak basal expression) in four urothelial carcinoma (UC) cell lines (RT112, VM-Cub-1, SW1710, and UM-UC-3) by mass spectrometry in comparison to their vector controls. We observed that HDAC5 expression in VM-Cub-1 triggered a drastic phenotype change from an epitheloid to a mesenchymal (i.e., epithelial-mesenchymal transition, EMT) and altogether diminished cell proliferation of the other three cell lines. Our mass-spec data are in line with the phenotypic transformation of VM-Cub-1. In addition, we also performed a protein expression profiling of HBLAK, a spontaneously immortalized from primary human bladder epithelial cells that can be directly compared with the four UC vector cells. HBLAK vector cells only were included for mass-spec as the cells failed to express HDAC5 after lentiviral transduction and selection.
2022-03-14 | PXD014448 | Pride
Project description:Aberrant expression of histone deacetylases (HDACs) and their activity are associated with a broad range of tumor development. However, based on cell or tissue types, class IIA HDACs such as HDAC4 and HDAC5 may facilitate or inhibit cancer progression. The goal of this project is to examine the gene expression changes caused by HDAC5 expression. Here, we studied the effects of stable expression of HDAC5 (that is normally downregulated or have a weak basal expression) in four urothelial carcinoma (UC) cell lines (RT112, VM-Cub-1, SW1710, and UM-UC-3) by rRNA-depleted RNA-sequencing in comparison to their vector controls. We observed that HDAC5 expression in VM-Cub-1 triggered a drastic phenotype change from an epitheloid to a mesenchymal (i.e., epithelial-mesenchymal transition, EMT) and altogether diminished cell proliferation of the other three cell lines. Our RNA-seq data are in line with the phenotypic transformation of VM-Cub-1. In addition, we also performed a gene expression profiling of HBLAK, a spontaneously immortalized from primary human bladder epithelial cells that can be directly compared with the four UC vector cells. HBLAK vector cells only were included for RNA-seq as the cells failed to express HDAC5 after lentiviral transduction and selection.
2019-11-13 | E-MTAB-8418 | biostudies-arrayexpress
Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).
2014-02-08 | E-GEOD-54785 | biostudies-arrayexpress
Project description:Previously published data suggested some redundant functions between HDAC1 and HDAC2 in mouse. To test this hypothesis, we used microarrays to have a genome wide analysis at the transcription level of primary MEFs lacking HDAC1, HDAC2. MEF HDAC1 F/F were were transduced with two different retroviruses: one virus expresses the Tamoxifen-inducible cre recombinase Cre-ERT2 and the second virus expresses either a small hairpin micro-RNA against HDAC2 or a scrambled version. HDAC1F/F MEFs expressing either a scrambled micro-RNA or a micro-RNA against HDAC2 can be induced by addition of Tamoxifen to delete HDAC1, thereby generating four different genotypes: WT, HDAC1 KO, HDAC2 knockdown (Kd) and HDAC1/2 KO/Kd.
2010-07-30 | E-GEOD-20100 | biostudies-arrayexpress
Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation
2014-02-08 | GSE54785 | GEO
Project description:The aim of our study is to determine the functions of histone deacetylases (HDACs) 1 and 2 in Schwann cells during postnatal development of the peripheral nervous system (PNS). Schwann cells are the myelinating glial cells of the PNS. At birth, mouse sciatic nerves mature in 2 subsequent phases: 1/ big caliber axons get sorted into a 1 to 1 relationship with Schwann cells, 2/ Schwann cells build a myelin sheath around sorted axons. In mice where both HDAC1 & HDAC2 have been specifically knocked out in Schwann cells, both phases are impaired. HDACs are chromatin remodeling enzymes, they can thus alter gene expression directly. We want to identify which genes controlled by HDAC1 and HDAC2 in Schwann cells are necessary for the maturation of sciatic nerves. Because HDAC1 and HDAC2 can compensate for each other loss to some extend, we will first analyze changes of gene expression in HDAC1/HDAC2 double KO animals. We expect to gain critical insights into the molecular mechanisms controlling Schwann cell differentiation and myelination. This knowledge is of key importance for the success of regenerative medicine in peripheral neuropathies, nerve tumors, and transplantation paradigms in non-regenerative CNS lesions and in large PNS injuries. 3 double knockout mutants for HDAC1 and HDAC2 and 3 control littermates were analyzed. Tissues analyzed: sciatic nerves of 2 day-old mouse pups
2011-02-25 | E-GEOD-27451 | biostudies-arrayexpress
Project description:We have performed quantitative proteomic TandemMassTag to investigate proteomic changes after deletion of epigenetic eraser genes Hdac1 and Hdac2 in intestinal epithelial cells. Both HDAC1 and HDAC2 are epigenetic erasers that drive specific and redundant gene expression patterns, in part by removing acetyl groups on histones. Deletion of these Hdac in intestinal epithelial cell (IEC) in vivo alters intestinal homeostasis, dependent on the Hdac deleted and the level of expression of both. To determine the specific IEC function of HDAC1 and HDAC2, we have performed transcriptomic and quantitative proteomic approaches on IEC deficient in Hdac1 and Hdac2. We have defined changes in both mRNA and protein expression patterns affecting IEC differentiation. We have identified IEC Hdac1- and Hdac2-dependent common as well as specific pathways and biological processes. These findings uncover unrecognized similarities and differences between Hdac1 and Hdac2 in IEC.
2021-09-09 | PXD022558 | Pride
Project description:Our studies demonstrated the critical role of Histone deacetylases (HDACs) in the regulation of nephrogenesis. To better understand the key pathways regulated by HDAC1/2 in early nephrogenesis, we performed chromatin immunoprecipitation sequencing (ChIP-Seq) of Hdac1/2 on isolated nephron progenitor cells (NPCs) from mouse E16.5 kidneys. Our analysis revealed that 11802 (40.4%) of Hdac1 peaks overlap with Hdac2 peaks, further demonstrates the redundant role of Hdac1 and Hdac2 during nephrogenesis. Common Hdac1/2 peaks are densely concentrated close to the transcriptional start site (TSS). GREAT Gene Ontology analysis of overlapping Hdac1/2 peaks reveals that Hdac1/2 are associated with metanephric nephron morphogenesis, chromatin assembly or disassembly, as well as other DNA checkpoints. Pathway analysis shows that negative regulation of Wnt signaling pathway is one of Hdac1/2’s most significant function in NPCs. Known motif analysis indicated that Hdac1 is enriched in motifs for Six2, Hox family, and Tcf family members, which are essential for self-renewal and differentiation of nephron progenitors. Interestingly, we found the enrichment of HDAC1/2 at the enhancer and promoter regions of actively transcribed genes, especially those concerned with NPC self-renewal. Hdac1/2 simultaneously activate or repress the expression of different genes to maintain the cellular state of nephron progenitors. We used the Integrative Genomics Viewer to visualize these target genes associated with each function and found that Hdac1/2 co-bound to the enhancers or/and promoters of genes associated with nephron morphogenesis, differentiation, and cell cycle control. Taken together, our ChIP-Seq analysis demonstrates that Hdac1/2 directly regulate the molecular cascades essential for nephrogenesis.
2022-11-07 | GSE217315 | GEO
Project description:Transcriptional profiling of mouse embryonic kidneys (E13.5) comparing UB HDAC1,2-/- kidneys with wild type kidneys. Studies in our lab showed that histone deacetylase 1 (HDAC1) and 2 (HDAC2) perform redundant, yet essential functions in the developing mouse ureteric bud (UB) tissue. Double deletion of HDAC1 and HDAC2 in the UB results in impaired UB branching morphogenesis, followed by severe kidney dysgenesis. The goal of the microarray analysis was to identify the genetic pathways controlled by HDAC1 and 2 in the UB.
2012-01-31 | GSE35432 | GEO