Biased Expression of the FOXP3Î3 Isoform in Aggressive Bladder Cancer Mediates Differentiation and Cisplatin Chemotherapy Resistance
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Kelvin Zhang
PROVIDER: E-GEOD-81157 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:This study shows for the first time that the FOXP3Δ3 isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal isoform is preferentially expressed in bladder cancer and induces a more aggressive and luminal regulation of cancer differentiation and the plasticity amongst cancer subtypes which can be leveraged to optimize therapeutic regimens. These findings also identify a novel molecular marker as a putative companion diagnostic to guide therapy and target to undermine chemotherapy resistance.
2016-08-05 | GSE81157 | GEO
Project description:Background: Muscle-invasive bladder cancer is a common aggressive disease with unmet clinical needs. Recent work established a set of consensus bladder cancer transcriptomic subtypes that distinguishes the cell identity of bladder cancers for improved diagnosis and treatment. However, how these distinct subtypes are regulated remains unclear. Given the link between super-enhancers and the regulation of cell identity, we hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of the various bladder cancer subtypes. Results: Through integrated RNA sequencing and epigenomic profiling of histone marks (H3K27ac, H3K27me3, H3K9me3) in a diverse panel of 15 primary bladder tumours, seven bladder cancer cell lines, and two primary cultures from normal human urothelia, we established the first integrated epigenetic map of bladder cancer and demonstrate the link between bladder cancer subtype and epigenetic control. Through H3K27ac analysis, we identify the repertoire of activated super-enhancers in bladder cancer that distinguish molecular subtypes. Building on these findings, we reveal the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal bladder cancer subgroups. We find that FOXA1, a key pioneer factor in Luminal bladder cancers identified in our Luminal transcription factor network, binds subgroup-specific bladder super-enhancers and correlates with their activation. Furthermore, CRISPR-Cas9 inactivating mutation of FOXA1 triggers a shift from Luminal to Basal cell identity. This shift is accompanied by an overexpression of ZBED2, one of the newly identified transcriptional regulators in the Basal-specific transcription factor network. 5Finally, we show that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in bladder cancer cells through STAT2 inhibition and promote cancer cell survival. Conclusions: Overall, our study provides new data for understanding epigenetic regulation of muscle- invasive bladder cancer and identifies a coregulated network of super-enhancers and associated transcription factors as new potential targets for the treatment of this aggressive disease
2023-06-27 | GSE195608 | GEO
Project description:Background: Muscle-invasive bladder cancer is a common aggressive disease with unmet clinical needs. Recent work established a set of consensus bladder cancer transcriptomic subtypes that distinguishes the cell identity of bladder cancers for improved diagnosis and treatment. However, how these distinct subtypes are regulated remains unclear. Given the link between super-enhancers and the regulation of cell identity, we hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of the various bladder cancer subtypes. Results: Through integrated RNA sequencing and epigenomic profiling of histone marks (H3K27ac, H3K27me3, H3K9me3) in a diverse panel of 15 primary bladder tumours, seven bladder cancer cell lines, and two primary cultures from normal human urothelia, we established the first integrated epigenetic map of bladder cancer and demonstrate the link between bladder cancer subtype and epigenetic control. Through H3K27ac analysis, we identify the repertoire of activated super-enhancers in bladder cancer that distinguish molecular subtypes. Building on these findings, we reveal the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal bladder cancer subgroups. We find that FOXA1, a key pioneer factor in Luminal bladder cancers identified in our Luminal transcription factor network, binds subgroup-specific bladder super-enhancers and correlates with their activation. Furthermore, CRISPR-Cas9 inactivating mutation of FOXA1 triggers a shift from Luminal to Basal cell identity. This shift is accompanied by an overexpression of ZBED2, one of the newly identified transcriptional regulators in the Basal-specific transcription factor network. 5Finally, we show that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in bladder cancer cells through STAT2 inhibition and promote cancer cell survival. Conclusions: Overall, our study provides new data for understanding epigenetic regulation of muscle- invasive bladder cancer and identifies a coregulated network of super-enhancers and associated transcription factors as new potential targets for the treatment of this aggressive disease
2024-05-23 | GSE195768 | GEO
Project description:Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and it is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells is sufficient to induce luminal-to-basal phenotypic switch implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal-basal fusions, and identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. Examination of histone H3K27Ac modifications in various breast cancer cell lines.
2015-06-10 | E-GEOD-69112 | biostudies-arrayexpress
Project description:The aim of the present study was to identify novel DNA methylation markers in bladder cancer (BCa) through genome-wide profiling of bladder cancer cell lines and subsequent MSP screening in urine samples. Experimental Design: MBD methylCap/seq was carried out to screen differentially methylated CpG islands using two BCa cell lines (5637 and T24) and two normal bladder mucosa (BM) samples. The top one hundred most hypermethylated targets were screened using Methylation Specific PCR (MSP) in small and big cohort of urine samples from BCa patients and normal controls. The diagnostic performance of the gene panel was further evaluated in different clinical scenarios. Results: In total, 1,627 gene promoter regions hypermethylated in BCa cell line were identified in genomic level methylation profiling. The followed screening procedure in clinical urine sample generated eight genes (VAX1, KCNV1, ECEL1, TMEM26, TAL1, PROX1, SLC6A20, and LMX1A) capable of differentiating BCa from normal control. Subsequent validation in a large sample size enabled the optimisation of 5 methylation targets (VAX1, KCNV1, TAL1, PPOX1 and CFTR) for BCa diagnosis with sensitivity and specificity of 86.32% and 87.13%, respectively. In addition, VAX1 and LMX1A methylation could predict the tumour recurrence. Conclusions: Tumor specific biomarkers of BCa could be established by first performing genome level methylation profiling with cell lines and then screening the potential targets in urine samples. The panel of methylated genes identified was promising for the early non-invasive detection and surveillance of BCa. MBD methylCap/seq was carried out to screen differentially methylated CpG islands using two BCa cell lines (5637 and T24), and two normal bladder tissue mix as control.
2012-04-30 | E-GEOD-33839 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. RNA-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment over time
2016-01-07 | E-GEOD-63582 | biostudies-arrayexpress
Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.
2020-09-15 | GSE157089 | GEO
Project description:Bladder cancer prognosis is closely linked to the underlying differentiation state of the tumor, ranging from the less aggressive and most differentiated luminal tumors to the more aggressive and least differentiated basal tumors. Sequencing of bladder cancer has revealed that loss-of-function mutations in chromatin regulators and mutations that activate receptor tyrosine kinase (RTK) signaling frequently occur in bladder cancer. However, little is known as to whether and how these two types of mutations functionally interact or cooperate to regulate tumor growth and differentiation state. Here, we focus on loss of the histone demethylase UTX (also known as KDM6A) and activation of the RTK FGFR3, two events that commonly co-occur in muscle invasive bladder tumors. We show that UTX loss and FGFR3 activation cooperate to disrupt the balance of luminal and basal gene expression in bladder cells. UTX localized to enhancers surrounding many genes that are important for luminal cell fate, and supported the transcription of these genes in a catalytic-independent manner. In contrast to UTX, FGFR3 activation was associated with lower expression of luminal genes in tumors and FGFR inhibition increased transcription of these same genes in cell culture models. This suggests an antagonistic relationship between UTX and FGFR3. In support of this model, UTX loss-of-function potentiated FGFR3-dependent transcriptional effects and the presence of UTX blocked an FGFR3-mediated increase in the colony formation of bladder cells. Taken together, our study reveals how mutations in UTX and FGFR3 converge to disrupt bladder differentiation programs that could serve as a therapeutic target.
2020-09-15 | GSE157090 | GEO
Project description:The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here, we describe a whole-genome transcriptome analysis of human benign prostatic basal and luminal populations by using deep RNA sequencing. Combined with comprehensive molecular and biological characterizations, we show that the differential gene expression profiles account for their distinct functional phenotypes. Strikingly, in contrast to luminal cells, basal cells preferentially express gene categories associated with stem cells, neural and neuronal development and RNA processing. Consistent with their expression profiles, basal cells functionally exhibit intrinsic stem-like and proneural properties with enhanced ribosome RNA (rRNA) transcription activity. Of clinical relevance, the treatment failed castration-resistant and anaplastic prostate cancers molecularly resemble a basal-like phenotype. Therefore, we link the cell-type specific gene signatures to subtypes of prostate cancer development, and identify genes associated with patient clinical outcome. Human total RNA profiles of 3 pairs of benign prostatic basal and luminal populations freshly purified from prostate tissues of three prostate cancer patients by deep RNA-seq.
2015-04-30 | E-GEOD-67070 | biostudies-arrayexpress
Project description:Basal-like breast cancer (BBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that BBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that basal but not luminal breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. BBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of BBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in BBC and CDK7 inhibition may be useful therapy for this challenging cancer. ChIP-Seq for H3K27ac in basal-like breast cancer and luminal-like breast cancer cell lines
2015-01-23 | E-GEOD-65201 | biostudies-arrayexpress