Ontology highlight
ABSTRACT:
PROVIDER: PRJNA255297 | ENA |
REPOSITORIES: ENA
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Project description:Alterations of chromatin modifiers are frequent in cancer but their functional consequences remain often unclear. Focusing on the Polycomb protein EZH2 that deposits H3K27me3 mark, we showed that its high expression in solid tumors is a consequence, and not a cause, of tumorigenesis. In mouse and human models, EZH2 is dispensable for prostate cancer development and restrains breast tumorigenesis. High EZH2 expression in tumors results from a tight coupling to proliferation to ensure H3K27me3 homeostasis. However, this process is malfunctioning in breast cancer. Low EZH2 expression relative to proliferation and mutations in Polycomb genes are actually of poor prognosis and occur in metastases. We show that while altered EZH2 activity consistently modulates a subset of its target genes, it promotes a wider transcriptional instability. Importantly, transcriptional changes consequent to EZH2 loss are predominantly irreversible. Our study provides an unexpected understanding of EZH2's contribution to solid tumors with important therapeutic implications.
2015-10-01 | GSE59427 | GEO
Project description:The Polycomb Group proteins foster gene repression profiles required for proper development and unimpaired adulthood, and comprise the components of the PRC2 complex including the histone H3 lysine 27 (H3K27) methyltransferase Ezh2. How mammalian PRC2 accesses chromatin is unclear. We find that Jarid2 associates with PRC2 and stimulates its enzymatic activity in vitro. Jarid2 contains a Jumonji C domain, but is devoid of detectable histone demethylase activity. Instead, its artificial recruitment to a promoter in vivo resulted in co-recruitment of PRC2 with resultant increased levels of H3K27me2/3. Jarid2 co-localizes with Ezh2 and MTF2, a homologue of Drosophila Pcl, at endogenous genes in ES cells. Jarid2 can itself bind DNA and its recruitment in ES cells is interdependent with that of PRC2 as Jarid2 knockdown reduced PRC2 at its target promoters, and ES cells devoid of the PRC2 component EED are deficient in Jarid2 promoter access. In addition to the well-documented defects in embryonic viability upon down-regulation of Jarid2, ES cell differentiation is impaired, as is Oct4 silencing. Examination of two factors in ES cells
2010-01-01 | E-GEOD-19708 | biostudies-arrayexpress
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
2019-05-03 | GSE130661 | GEO
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
2019-05-06 | GSE130738 | GEO
Project description:Perturbations in histone modifications alter transcription and promote carcinogenesis. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the mechanisms driving EZH2 overexpression are obscure and elucidating the role of PRC2 in breast cancer, which is highly heterogeneous, is challenging given its context-dependent oncogenic and tumor suppressive functions. Here, using genetically engineered mouse, PDX and cell line models, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 subunit overexpression via control of mRNA translation. In breast cancers initiated by the oncogene ErbB2, c-Src stimulates mitochondrial ATP production to suppress energy stress and permit sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumorigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
2018-01-31 | GSE93892 | GEO
Project description:Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Here, we identified the transcriptional complex, NELF (Negative elongation factor), as an important regulator of this process. Using cancer cell lines and patient-derived tumor organoids, we demonstrated that loss of NELF inhibits breast cancer tumorigenesis and metastasis. Specifically, we found that epithelial-mesenchymal transition (EMT) and stemness-associated genes are downregulated in NELF-depleted breast cancer cells. Quantitative Multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) of NELF-E, a key subunit of NELF, reveals significant rewiring of NELF-E-associated chromatin partners as a function of EMT, and further illuminates a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E led to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identified the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate expression of critical EMT marker genes, phenocopying NELF ablation. Elevated NELF-E and KAT2B expressions are associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Importantly, KAT2B knockout mice are viable, raising the exciting prospect of targeting this dependency therapeutically. Taken together, we uncovered a crucial role of the NELF-E-KAT2B epigenetic axis in breast cancer carcinogenesis.
2023-01-28 | PXD031304 | JPOST Repository
Project description:ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here we show that frequent deletions (~30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer (CRC) cause impaired PARP1 transferase activity in a gene dosage-dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage, and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human CRC xenografts. MACROD2 deletion in sporadic CRC is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability thereby driving cancer evolution.
2018-06-05 | GSE115145 | GEO
Project description:DCD is a gene amplified and overexpressed in a subset of breast tumors acting as a growth and survival factor. Patients with DCD-positive breast cancer have worse prognostic features. To investigate the role of DCD in breast tumorigenesis, we analyzed the consequences of its downregulation in human breast cancer cell lines using three specific shRNA lentivirus vectors. Genes up- and down-regulated by DCD were identified using Affymetrix microarray and analyzed by MetaCore Platform. We found that loss of DCD expression led to reduced cell proliferation, resistance to apoptosis, and suppressed tumorigenesis in immunodeficient mice. Network analysis of gene expression data revealed perturbed ERBB signaling following DCD shRNA expression including changes in the expression of ERBB receptors and their ligands. These findings imply that DCD promotes breast tumorigenesis via modulating the activity of the ERBB signaling pathways. As ERBB signaling is also important for neural survival, HER2+ breast tumors may highjack DCD’s neural survival-promoting functions to promote tumorigenesis.
2015-08-12 | GSE57578 | GEO
Project description:Oestrogen receptor-α (ER) is the principal transcription factor in the majority of breast cancers, driving expression of genes that control cell growth and endocrine response. Understanding the mechanisms of ER action is crucial for improving response to endocrine treatments. Recent studies show that cytosine deaminase (CD) activity is an important source of cancer mutations. In particular, APOBEC3B (A3B) promotes mutagenesis in breast cancer cells1. Our analysis of breast cancer expression datasets showed that A3B expression predicts for poor survival in ER-positive, but not in ER-negative patients, indicative of a link with ER activity. Chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq) used to map global A3B binding sites showed a remarkable oestrogen-stimulated recruitment of A3B to ER binding sites. Functionally, A3B was critical for ER transcriptional activity and regulated breast cancer cell proliferation. We show that A3B regulates ER transcription by promoting cytosine deamination and activation of DNA strand break repair at ER binding regions. We propose that cytosine deamination and DNA strand break generation by A3B facilitates gene expression by aiding chromatin remodeling at ER target genes. Our findings also suggest a mechanism by which subversion of transcription factor mediated recruitment of cytosine deaminases promotes cancer mutations. Hormone-depleted MCF-7 breast cancer cell line was treated with estrogen (100 nM), H2O2 (10 mM) or vehicle for 45 minutes. H2AX ChIP-seq was performed using Illumina methodology.
2015-09-07 | E-GEOD-57426 | biostudies-arrayexpress
Project description:Using transgenic mouse models of breast cancer, we demonstrate that loss of ShcA signaling within mammary tumors results in extensive CD4+ T cell infiltration, activation and induction of a humoral immune response. Our studies reveal that ShcA signaling during early breast cancer progression is required to establish and maintain an immunosuppressive state that favors tumor growth. Consistent with these transgenic studies, high ShcA levels correlate with poor outcome and reduced CTL infiltration in primary human breast cancers. Conversely, elevated expression of a ShcA-regulated immune signature, generated from ShcA-null mammary tumors, is a predictor of good prognosis in HER2-positive and basal breast cancer patients. These observations define a novel role for ShcA in polarizing the immune response to facilitate tumorigenesis NIC SHC null Tumors vs. pooled MMPV-NIC reference, some replicate dye swaps
2010-10-12 | E-GEOD-18996 | biostudies-arrayexpress