Promoter-centric gene regulation in drug-resistant cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE288780 | GEO | 2025/02/12
REPOSITORIES: GEO
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Project description:Multiple gene expression studies have demonstrated that breast cancer biological diversity is associated with distinct transcriptional programs. Transcription factors, because of their unique ability to coordinate the expression of multiple genes, are speculated to play a role in generating phenotypic plasticity associated with cancer progression including acquired drug resistance. Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust means for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to a fulvestrant, a clinically important anti-endocrine therapeutic agent. We isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor positive breast cancer cell lines. Comparative gene expression profile analysis of the ZF-TF-transduced breast cancer cell lines revealed a 72-gene cluster that constituted a common signature for the fulvestrant-resistance phenotype. Pathway enrichment-analysis of gene expression data revealed that the ZF-TF-induced fulvestrant resistance is associated with an estrogen receptor negative-like gene set and four unique myb-regulated gene sets. Furthermore, we identified a set of genes strongly expressed in the ZF-TF-induced fulvestrant-resistant cells that was correlated with a lower probability of distant metastasis-free or death-from-relapse-free survival of breast cancer patients. MCF7-R73 cells, a monoclonal MCF7 subline that is highly sensitive to fulvestrant-induced cytocidal activity, underwent retroviral transduction with the zinc finger transcription factor (ZF-TF) activator library or with a control plasmid encoding only the NF-kB p65 activation domain. Both populations of cells were enriched for transduced cells by selecting for growth in puromycin and for fulvestrant-resistant cells by selecting with 100 nM fulvestrant. After 6 weeks of continuous treatment with fulvestrant, hundreds of drug-resistant colonies emerged from the population of cells infected with the ZF-TF activator library. By contrast, as expected, the control MCF7cell line transduced by NF-kB p65-only underwent massive cell death resulting in the complete absence of resistant colonies. DNA encoding the zinc-finger arrays was rescued by PCR from genomic DNA of pooled fulvestrant-resistant cells. The sequences of the ZF-TFs were determined and 46 unique ZF-TF clones identified. These 46 unique ZF-TFs were re-cloned into the retroviral vector and converted into clonal virus stocks that were used to transduce MCF7-R73 cells. These 46 retrovirally transduced cell populations were then challenged with fulvestrant. As compared with the control MCF-238 cells, MCF7-R73 cells transduced with six unique ZF-TFs demonstrated survival and growth in the presence of 100nM fulvestrant.
2011-07-17 | E-GEOD-27444 | biostudies-arrayexpress
Project description:Abstract: Bacteria adapt to the constantly changing environments largely by transcriptional regulation through the activities of various transcription factors (TFs). However, techniques that monitor the in situ TF-promoter interactions in living bacteria are lacking. Herein, we developed a whole-cell TF-promoter binding assay based on the intermolecular Förster resonance energy transfer (FRET) between a fluorescent unnatural amino acid CouA which is genetically encoded into defined sites in TFs and the live cell fluorescent nucleic acid stain SYTO 9. We show that this new FRET pair monitors the intricate TF-promoter interactions elicited by various types of signal transduction systems with specificity and sensitivity. Furthermore, the assay is applicable to identify novel modulators of the regulatory systems of interest and monitor TF activities in bacteria colonized in C. elegans. In conclusion, we established a tractable and sensitive TF-promoter binding assay in living bacteria which not only complements currently available approaches for DNA-protein interactions but also provides novel opportunities for functional annotation of bacterial signal transduction systems and studies of the bacteria-host interface
2022-10-13 | PXD030973 | Pride
Project description:Phenotypic plasticity has emerged as an important mechanism of therapy resistance in cancers, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ER-alpha and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems support a coordinate role of GATA3 and AP1 in enhancer reprogramming that drives phenotypic plasticity to achieve endocrine resistance or cancer invasive progression. Thus, changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression
2019-05-24 | MSV000083857 | MassIVE
Project description:Although widely used in chemotherapy for colon cancer, 5-fluorouracil (5-FU) resistance is the main reason greatly limiting the efficacy of current therapies, leading to poor patient prognosis and survival. Histone lysine succinylation plays a vital role in various diseases by influencing gene expression and chromatin structure. However, limited information is currently available about the role of H3K23 succinylation associated with 5-FU resistance in colon cancer cells (CCCs). Here we explored the systematic alterations of H3K23s succinylation using the Cleavage Under Targets and Tagmentation (CUT&Tag), followed by integrated analysis of multi-omics data to identify potential regulators and their targets associated with differentially enriched regions (DERs) in the parental and 5-FU-resistant HCT15 colon cancer cells. More than 60,000 high-quality peaks were obtained from each sample with higher signal enriched at gene promoter regions. A total of 13,622 H3K23su DERs were identified in 5-FU-resistant HCT15 cells compared to control, which was positively (r = 0.68) correlated with their nearest differentially expressed genes (DEGs). The up-regulated DEGs associated with H3K23su GAIN regions are mainly involved in colorectal cancer, MAPK, Ras, and p53 signaling pathways, while the down-regulated DEGs related to H3K23su LOSS regions significantly enriched in the signaling pathways of Wnt and HIF-1. DNA motif analyses of the DER sequences showed that, besides AP-1, the members of FOX, GATA, and TEAD transcription factor (TF) families were potentially enriched in GAIN or LOSS regions with different preferences. Moreover, differentially expressed TFs and their potential targets associated with H3K23su DERs were identified, including FOSL21, FOXA1 and HNF1B, and known and predicted interactions among these critical TFs were further illustrated. These data provided clear insights and resources for an improved understanding of the role of H3K23su related to 5-FU resistance in colon cancer cells based on the multi-omics data, which allowed for the detection of epigenomic profiles, potential regulatory TFs, cis-regulatory elements, and therapeutic targets.
2023-06-20 | GSE234735 | GEO
Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.
2014-05-24 | E-GEOD-57930 | biostudies-arrayexpress
Project description:Multiple gene expression studies have demonstrated that breast cancer biological diversity is associated with distinct transcriptional programs. Transcription factors, because of their unique ability to coordinate the expression of multiple genes, are speculated to play a role in generating phenotypic plasticity associated with cancer progression including acquired drug resistance. Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust means for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to a fulvestrant, a clinically important anti-endocrine therapeutic agent. We isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor positive breast cancer cell lines. Comparative gene expression profile analysis of the ZF-TF-transduced breast cancer cell lines revealed a 72-gene cluster that constituted a common signature for the fulvestrant-resistance phenotype. Pathway enrichment-analysis of gene expression data revealed that the ZF-TF-induced fulvestrant resistance is associated with an estrogen receptor negative-like gene set and four unique myb-regulated gene sets. Furthermore, we identified a set of genes strongly expressed in the ZF-TF-induced fulvestrant-resistant cells that was correlated with a lower probability of distant metastasis-free or death-from-relapse-free survival of breast cancer patients.
2011-07-18 | GSE27444 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246590 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246583 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246581 | GEO
Project description:TEAD transcription factors (TEAD1-4) serve as the primary effectors of the Hippo signaling pathway in various cancers. There has been significant progress in the development of therapeutic strategies aimed at disrupting the interaction of TEAD with its coactivators YAP/TAZ. However, targeted therapy leads to the emergence of resistance which poses a barrier to achieving complete cures. Currently, the underlying mechanism of resistance to TEAD inhibition in cancers remains unexplored. We uncover that upregulation of the AP-1 transcription factors, along with restored YAP/TEAD activity, drives resistance to GNE-7883, a pan-TEAD and allosteric TEAD inhibitor. Acute GNE-7883 treatment abrogates YAP binding and attenuates FOSL1 activity but compensation by increased MAPK pathway activity remains insufficient for cell survival. In contrast, TEAD inhibitor resistant cells are able to restore YAP and TEAD occupancy and acquire additional FOSL1 binding sites, leading to increased chromatin accessibility at AP-1 motifs. Resistant cells undergo transcriptional reprogramming to acquire a mesenchymal-like cell state and sustained MAPK activity. We uncover a dependence on the MAPK pathway in the TEAD inhibitor resistant cells, further highlighting the key role of MAPK pathway inhibitors, such as Cobimetinib and Belvarafenib to mitigate resistance mechanisms to TEAD inhibition in Hippo pathway dependent cancers. This study describes a clinically relevant interplay between the Hippo and MAPK pathway in cancers and offers a promising avenue to address TEAD inhibitor resistance in the clinic.
2024-12-17 | GSE246578 | GEO