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CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [ChIP-seq]

ABSTRACT: Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression, but remains poorly understood. We found that the uncharacterized epigenetic factor Chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a functional role for CDYL2 in malignancy, it positively regulated breast cancer cell migration, invasion, stem-like phenotypes, and epithelial-to-mesenchymal transition (EMT). CDYL2 regulation of these plasticity-associated processes depended on signaling via p65/NF-kB and STAT3. This, in turn, was downstream of CDYL2 regulation of MIR124 gene transcription. CDYL2 co-immunoprecipitated with G9a/EHMT2 and GLP/EHMT1, and regulated the chromatin enrichment of G9a and EZH2 at MIR124 genes. We propose that CDYL2 contributes to poor prognosis in breast cancer by recruiting G9a and EZH2 to epigenetically repress MIR124 genes, thereby promoting NF-kB and STAT3 signaling, as well as downstream cancer cell plasticity and malignant progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150274 | GEO | 2020/05/17

REPOSITORIES: GEO

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CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [MDA-MB-231 RNA-seq]

Project description:Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression, but remains poorly understood. We found that the uncharacterized epigenetic factor Chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a functional role for CDYL2 in malignancy, it positively regulated breast cancer cell migration, invasion, stem-like phenotypes, and epithelial-to-mesenchymal transition (EMT). CDYL2 regulation of these plasticity-associated processes depended on signaling via p65/NF-kB and STAT3. This, in turn, was downstream of CDYL2 regulation of MIR124 gene transcription. CDYL2 co-immunoprecipitated with G9a/EHMT2 and GLP/EHMT1, and regulated the chromatin enrichment of G9a and EZH2 at MIR124 genes. We propose that CDYL2 contributes to poor prognosis in breast cancer by recruiting G9a and EZH2 to epigenetically repress MIR124 genes, thereby promoting NF-kB and STAT3 signaling, as well as downstream cancer cell plasticity and malignant progression.

2020-05-17 | GSE150319 | GEO

CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [RNA-seq]

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CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity

Project description:CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity

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CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [RNA-seq]

Project description:CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [RNA-seq]

| PRJNA631744 | ENA

CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [ChIP-seq]

Project description:CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [ChIP-seq]

| PRJNA631707 | ENA

CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [MDA-MB-231 RNA-seq]

Project description:CDYL2 epigenetically regulates MIR124 to control NF-kB/STAT3-dependent breast cancer cell plasticity [MDA-MB-231 RNA-seq]

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An EZH2-NF-kB Regulatory Axis Drives Expression of Pro-Oncogenic Genetic Signatures in TNBC

Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.

2023-07-10 | GSE223959 | GEO

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

SWATH proteomic profiling of prostate cancer cells identifies NUSAP1 as a biomarker of response to Galiellalactone

Project description:Galiellalactone (GL) is a fungal metabolite that presents antitumor and anti-inflammatory activities in vitro and in vivo. Previous studies have shown that GL targets NF-KB and STAT3 pathways and induces G2/M cell cycle arrest in androgen-insensitive prostate cancer cells. In this study, we show that GL-induced cell cycle arrest is independent of the NF-KB and STAT3 pathways in DU145 and PC-3 cells, and also that GL did not affect cell cycling in androgen-sensitive prostate cancer cell such as LNCaP and 22Rv1 cells. In addition, we showed confluence resistance to GL in DU145 cells. Using a SWATH proteomic approach we identified the down-regulation of Nucleolar and spindle associated protein 1 (NUSAP1) under DU145 confluence and in LNCaP cells. Also, the inhibition of NUSAP1 by siRNAs induced resistance to GL in DU145 cells, suggesting that NUSAP1 may be a target for GL and could be useful as biomarker for responsiveness of the antitumor activity of GL.

2019-01-14 | PXD010993 | Pride

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