Pattern occupation of HDACs on chromatin determines PI3K/AKT inhibitor resistance in cancers [RNA-seq]
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PROVIDER: PRJNA564800 | ENA |
REPOSITORIES: ENA
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Project description:Pattern occupation of HDACs on chromatin determines PI3K/AKT inhibitor resistance in cancers [ChIP-seq]
| PRJNA564807 | ENA
Project description:Blocking BRD4 or HDACs induces paradoxically similar gene expression, comparably attenuates PI3K/AKT inhibitor resistance in multiple cancer cells.
2020-09-09 | GSE137207 | GEO
Project description:Blocking BRD4 or HDACs induces paradoxically similar gene expression, comparably attenuates PI3K/AKT inhibitor resistance in multiple cancer cells.
2020-09-09 | GSE137200 | GEO
Project description:Acquisition of resistance to PI3K/AKT-targeted monotherapy regardless of cancer types implies the existence of common mechanisms. Here we demonstrate that while causing glycolysis crisis, acetyl-CoA shortage and global decrease of histone acetylation, PI3K/AKT inhibitors induce drug resistance by selectively augmenting CBP/p300, H3K27 acetylation and BRD4 binding at genomic loci of a subset of growth factor and receptor (GF/R) genes. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDACs at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers a general solution to overcome PI3K/AKT inhibitor resistance in different cancers.
2020-09-09 | GSE147455 | GEO
Project description:The insulin/IGF-IRS-PI3K-Akt pathway is highly conserved in evolution. To test whether this signaling cascade determines organ size in vertebrates, we have recently created mouse lines transgenic for constitutively active (caPI3K) and dominant-negative forms of PI3K (dnPI3K) (Shioi et al., 2000). Transgene expression is driven by the cardiac-specific a -myosin heavy chain (MHC) promoter. Both transgenic lines are characterized by moderate but highly consistent changes in heart size, despite the fact that body weight and the size of other organs are completely normal. caPI3K transgenic animals have hearts 20% larger than those of wild type littermates, whereas dnPI3K mice have hearts that are 17% smaller. The observed changes in heart size correlate with an appropriate increase or decrease in the size of transgenic cardiomyocytes. These hearts do not have cardiomyopathic changes, since the contractile function of transgenic hearts is normal, and signs of necrosis, apoptosis, or interstitial fibrosis are absent (see Physiology). These data suggest an autonomous role for PI3K in cell size regulation. Our goal is now to determine how activation of this system translates into changes in cell size by identifying the trigger and components of this signaling cascade. Heterozygous caPI3K (constitutively active PI3K) and dnPI3K (dominant-negative PI3K) transgenic female mice (5-14 months) compared with non-transgenic littermates. Transgene expression driven by the a -myosin heavy chain (a -MHC) promoter.
2007-12-13 | E-GEOD-558 | biostudies-arrayexpress
Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE35701: CP001: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy GSE35703: CP003: Modulation of glutamine metabolism by the PI3K-PKB/c-akt-FOXO network regulates autophagy Refer to individual Series
2012-07-21 | E-GEOD-35705 | biostudies-arrayexpress
Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress
Project description:Ectopic TAL1 expression is frequently associated with PI3K-AKT pathway mutations in T-ALL. Here we developed inducible mouse models demonstrating cooperation between TAL1 and PI3K-AKT signaling and we used these models to study the effects of targeted inhibitors.
2022-04-02 | GSE199823 | GEO
Project description:Understanding the crosstalk between malignant B-cells and their milieu could provide clues on the molecular and clinical biology of Chronic Lymphocytic Leukemia (CLL). Aiming to generate novel therapeutic strategies, different groups have studied different CLL proliferative fractions. We previously, identified one of these proliferative subsets in the peripheral blood from progressive unmutated CLL patients. Since the presence of this small subset appears to be a hallmark of a proliferative disease in which B lymphocytes are being constitutively activated in the proliferative centers of these patients, we performed gene expression analysis comparing the global mRNA and microRNAs expression of this leukemic subpopulation. Our results suggest that the proliferative behaviour of this fraction appears to depend on microRNA-22 over-expression, which induces PTEN downregulation and PI3K/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B-cells switches on PI3K/AKT leading to FOXO1 inactivation, p27-Kip1 downregulation, and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40L/IL4 and more importantly, that this regulatory loop is also present in lymph nodes from progressive UM patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide rationale for the usage of PI3K inhibitors. Two-subset of B cells, QF vs PF. 8 samples of 4 patients.
2014-05-15 | E-GEOD-53236 | biostudies-arrayexpress