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Context-Specific Regulation of NF-?B Target Gene Expression by EZH2 in Breast Cancers

ABSTRACT: Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in repressing NF-κB targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-κB targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers. 12 samples were analyzed including three replicates of siNC CTRL and siEZH2 CTRL.

ORGANISM(S): Homo sapiens

SUBMITTER: Guan Peiyong

PROVIDER: S-ECPF-GEOD-30670 | biostudies-other |

REPOSITORIES: biostudies-other

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Context-Specific Regulation of NF-?B Target Gene Expression by EZH2 in Breast Cancers

Project description:Both EZH2 and NF-?B contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-?B target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-?B targets. Intriguingly, EZH2 acts oppositely in repressing NF-?B targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-?B targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers. 12 samples were analyzed including three replicates of siNC CTRL and siEZH2 CTRL.

2011-08-14 | E-GEOD-30670 | biostudies-arrayexpress

Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers

Project description:Both EZH2 and NF-κB contribute to aggressive breast cancer, yet whether the two oncogenic factors have functional cross-talk in breast cancer is largely unknown. Here, we uncover an unexpected role of EZH2 in conferring the constitutive activation of NF-κB target gene expression in ER-negative basal-like breast cancer cells. This function of EZH2 is independent of its histone methyltransferase activity but requires the physical interaction with RelA/RelB to promote the expression of NF-κB targets. Intriguingly, EZH2 acts oppositely in repressing NF-κB targets in ER-positive luminal-like breast cancer cells by interacting with ER and directing repressive histone methylation. Thus, EZH2 function as a double-facet molecule in breast cancers, functioning either as a transcriptional activator or repressor of NF-κB targets, in a cell context-dependent manner. These findings reveals an additional mechanism by which EZH2 promotes breast cancer progression and also underscore the need for developing context-specific strategy for therapeutic targeting of EZH2 in breast cancers.

2011-08-15 | GSE30670 | GEO

EZH2 regulates expression of FOXC1 by mediating H3K27me3 in breast cancers.

Project description:Triple-negative breast cancer (TNBC) is characterized by low expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER), and progesterone receptor (PR), which is the most aggressive subtype with poor outcome among breast cancers. The underlying mechanisms of TNBC remain unclear and there is a lack of biomarkers. In this study we conducted an in silico assay and found that FOXC1 was highly expressed in ER-/PR-/HER2- breast cancers, which was confirmed by qRT-PCR, immunohistochemistry, and Western blot analysis. FOXC1 was more highly expressed in TNBCs than the other breast cancers. Kaplan-Meier plotter revealed that expression of FOXC1 was associated with overall survival (OS) of patients with breast cancers. Expression of FOXC1 was reversely associated with level of H3K27me3, which was methylated by EZH2. In MCF-7 and T47D cells, inhibition of EZH2 by DZNeP or GSK343 concentration- and time-dependently increased expression of FOXC1. Finally, we demonstrated that the expression of FOXC1 was associated with resistance of doxorubicin treatment of breast cancer cells. In conclusion, these results suggest that FOXC1 may be a potential biomarker or drug target for TNBCs, and that downregulation of FOXC1 could have therapeutic value in treatment of TNBCs.

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Context-specific role of SOX9 in NF-Y mediated gene regulation in colorectal cancer cells.

Project description:Roles for SOX9 have been extensively studied in development and particular emphasis has been placed on SOX9 roles in cell lineage determination in a number of discrete tissues. Aberrant expression of SOX9 in many cancers, including colorectal cancer, suggests roles in these diseases as well and recent studies have suggested tissue- and context-specific roles of SOX9. Our genome wide approach by chromatin immunoprecipitation sequencing (ChIP-seq) in human colorectal cancer cells identified a number of physiological targets of SOX9, including ubiquitously expressed cell cycle regulatory genes, such as CCNB1 and CCNB2, CDK1, and TOP2A. These novel high affinity-SOX9 binding peaks precisely overlapped with binding sites for histone-fold NF-Y transcription factor. Furthermore, our data showed that SOX9 is recruited by NF-Y to these promoters of cell cycle regulatory genes and that SOX9 is critical for the full function of NF-Y in activation of the cell cycle genes. Mutagenesis analysis and in vitro binding assays provided additional evidence to show that SOX9 affinity is through NF-Y and that SOX9 DNA binding domain is not necessary for SOX9 affinity to those target genes. Collectively, our results reveal possibly a context-dependent, non-classical regulatory role for SOX9.

| S-EPMC4513854 | biostudies-literature

Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit.

Project description:The p52/p100 nuclear factor kappa B (NF-kappaB) subunit (NF-kappaB2) is aberrantly expressed in many tumour types and has been implicated as a regulator of cell proliferation. Here, we demonstrate that endogenous p52 is a direct regulator of Cyclin D1 expression. However, stimulation of Cyclin D1 expression alone cannot account for all the cell cycle effects of p52/p100 and we also find that p52 represses expression of the Cyclin-dependent kinase inhibitor p21(WAF/CIP1). Significantly, this latter effect is dependent upon basal levels of the tumour suppressor p53. By contrast, p52 cooperates with p53 to regulate other known p53 target genes such as PUMA, DR5, Gadd45alpha and Chk1. p52 associates directly with these p53-regulated promoters where it regulates coactivator and corepressor binding. Moreover, recruitment of p52 is p53 dependent and does not require p52-DNA-binding activity. These results reveal a complex role for p52 as regulator of cell proliferation and p53 transcriptional activity. Furthermore, they imply that in some cell types, p52 can regulate p53 function and influence p53-regulated decision-making following DNA damage and oncogene activation.

| S-EPMC1618099 | biostudies-literature

Foxh1/Nodal Defines Context-Specific Direct Maternal Wnt/β-Catenin Target Gene Regulation in Early Development.

Project description:Although Wnt/β-catenin signaling is generally conserved and well understood, the regulatory mechanisms controlling context-specific direct Wnt target gene expression in development and disease are still unclear. The onset of zygotic gene transcription in early embryogenesis represents an ideal, accessible experimental system to investigate context-specific direct Wnt target gene regulation. We combine transcriptomics using RNA-seq with genome-wide β-catenin association using ChIP-seq to identify stage-specific direct Wnt target genes. We propose coherent feedforward regulation involving two distinct classes of direct maternal Wnt target genes, which differ both in expression and persistence of β-catenin association. We discover that genomic β-catenin association overlaps with Foxh1-associated regulatory sequences and demonstrate that direct maternal Wnt target gene expression requires Foxh1 function and Nodal/Tgfβ signaling. Our results support a new paradigm for direct Wnt target gene co-regulation with context-specific mechanisms that will inform future studies of embryonic development and more widely stem cell-mediated homeostasis and human disease.

| S-EPMC7347983 | biostudies-literature

Combinatorial pharmacologic approaches target EZH2-mediated gene repression in breast cancer cells.

Project description:Polycomb protein EZH2-mediated gene silencing is implicated in breast tumorigenesis through methylation of histone H3 on Lysine 27 (H3K27). We have previously shown that S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A can modulate histone methylation and disrupt EZH2 complex. Here, we used 3-deazaneplanocin A, together with other chromatin remodeling agents, as well as RNA interference-mediated EZH2 depletion, to probe the role of EZH2 in coordination with other epigenetic components in gene regulation in breast cancer cells. Through genome-wide gene expression analysis, coupled with extensive chromatin immunoprecipitation analysis of histone modifications, we have identified a variety of gene sets that are regulated either by EZH2 alone or through the coordinated action of EZH2 with HDAC and/or DNA methylation. We further found that tumor antigen GAGEs were regulated by distinct epigenetic mechanisms in a cell context-dependent manner, possibly reflecting mechanistic heterogeneity in breast cancer. Intriguingly, we found that EZH2 regulates a remarkable cohort of genes whose functions are highly enriched in immunoresponse and autocrine inflammation network, and that their transcriptional activation upon EZH2 perturbation is cancer specific, revealing a potential novel role of EZH2 in regulating cancer immunity. These findings show the complexity and diversity of epigenetic regulation in human cancer and underscore the importance for developing combinatorial pharmacologic approaches for effective epigenetic gene reactivation.

| S-EPMC2794891 | biostudies-literature

Signal transduction controls heterogeneous NF-?B dynamics and target gene expression through cytokine-specific refractory states.

Project description:Cells respond dynamically to pulsatile cytokine stimulation. Here we report that single, or well-spaced pulses of TNF? (>100?min apart) give a high probability of NF-?B activation. However, fewer cells respond to shorter pulse intervals (<100?min) suggesting a heterogeneous refractory state. This refractory state is established in the signal transduction network downstream of TNFR and upstream of IKK, and depends on the level of the NF-?B system negative feedback protein A20. If a second pulse within the refractory phase is IL-1? instead of TNF?, all of the cells respond. This suggests a mechanism by which two cytokines can synergistically activate an inflammatory response. Gene expression analyses show strong correlation between the cellular dynamic response and NF-?B-dependent target gene activation. These data suggest that refractory states in the NF-?B system constitute an inherent design motif of the inflammatory response and we suggest that this may avoid harmful homogenous cellular activation.

| S-EPMC4935804 | biostudies-literature

Regulation of p53 and Rb links the alternative NF-?B pathway to EZH2 expression and cell senescence.

Project description:There are two major pathways leading to induction of NF-?B subunits. The classical (or canonical) pathway typically leads to the induction of RelA or c-Rel containing complexes, and involves the degradation of I?B? in a manner dependent on I?B kinase (IKK) ? and the IKK regulatory subunit NEMO. The alternative (or non-canonical) pathway, involves the inducible processing of p100 to p52, leading to the induction of NF-?B2(p52)/RelB containing complexes, and is dependent on IKK? and NF-?B inducing kinase (NIK). Here we demonstrate that in primary human fibroblasts, the alternative NF-?B pathway subunits NF-?B2 and RelB have multiple, but distinct, effects on the expression of key regulators of the cell cycle, reactive oxygen species (ROS) generation and protein stability. Specifically, following siRNA knockdown, quantitative PCR, western blot analyses and chromatin immunoprecipitation (ChIP) show that NF-?B2 regulates the expression of CDK4 and CDK6, while RelB, through the regulation of genes such as PSMA5 and ANAPC1, regulates the stability of p21WAF1 and the tumour suppressor p53. These combine to regulate the activity of the retinoblastoma protein, Rb, leading to induction of polycomb protein EZH2 expression. Moreover, our ChIP analysis demonstrates that EZH2 is also a direct NF-?B target gene. Microarray analysis revealed that in fibroblasts, EZH2 antagonizes a subset of p53 target genes previously associated with the senescent cell phenotype, including DEK and RacGAP1. We show that this pathway provides the major route of crosstalk between the alternative NF-?B pathway and p53, a consequence of which is to suppress cell senescence. Importantly, we find that activation of NF-?B also induces EZH2 expression in CD40L stimulated cells from Chronic Lymphocytic Leukemia patients. We therefore propose that this pathway provides a mechanism through which microenvironment induced NF-?B can inhibit tumor suppressor function and promote tumorigenesis.

| S-EPMC4177746 | biostudies-literature

Context-specific gene regulatory networks subdivide intrinsic subtypes of breast cancer.

Project description:Breast cancer is a highly heterogeneous disease with respect to molecular alterations and cellular composition making therapeutic and clinical outcome unpredictable. This diversity creates a significant challenge in developing tumor classifications that are clinically reliable with respect to prognosis prediction.This paper describes an unsupervised context analysis to infer context-specific gene regulatory networks from 1,614 samples obtained from publicly available gene expression data, an extension of a previously published methodology. We use the context-specific gene regulatory networks to classify the tumors into clinically relevant subgroups, and provide candidates for a finer sub-grouping of the previously known intrinsic tumors with a focus on Basal-like tumors. Our analysis of pathway enrichment in the key contexts provides an insight into the biological mechanism underlying the identified subtypes of breast cancer.The use of context-specific gene regulatory networks to identify biological contexts from heterogenous breast cancer data set was able to identify genomic drivers for subgroups within the previously reported intrinsic subtypes. These subgroups (contexts) uphold the clinical relevant features for the intrinsic subtypes and were associated with increased survival differences compared to the intrinsic subtypes. We believe our computational approach led to the generation of novel rationalized hypotheses to explain mechanisms of disease progression within sub-contexts of breast cancer that could be therapeutically exploited once validated.

| S-EPMC3073183 | biostudies-literature

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