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Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [MCF7]

ABSTRACT: MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61720 | GEO | 2014/09/30

SECONDARY ACCESSION(S): PRJNA261954

REPOSITORIES: GEO

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Similar Datasets

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [MCF7]

Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. miRNA profiling of MCF7 cells in normal or hypoxic conditions or after DICER knockdown in MCF7 cells.

2014-09-30 | E-GEOD-61720 | biostudies-arrayexpress

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [HMLER]

Project description:MicroRNAs are small regulatory RNAs that post-transcriptionally control gene expression. Reduced expression of DICER, the enzyme involved in microRNA processing, is frequently observed in cancer and is associated with poor clinical outcome in various malignancies. Yet the underlying mechanisms are not well understood. Here, we identify tumor hypoxia as a regulator of DICER expression in large cohorts of breast cancer patients. We show that DICER expression is suppressed by hypoxia through an epigenetic mechanism that involves inhibition of oxygen-dependent H3K27me3 demethylases KDM6A/B and results in silencing of the DICER promoter. Subsequently, reduced miRNA processing leads to derepression of the miR-200 target ZEB1, stimulates the epithelial to mesenchymal transition and ultimately results in the acquisition of stem cell phenotypes in human mammary epithelial cells. Our study uncovers a previously unknown relationship between oxygen-sensitive epigenetic regulators, miRNA biogenesis and tumor stem cell phenotypes that may underlie poor outcome in breast cancer. A total of 12 samples were analyzed. For each condition tested, 3 independent experiments were carried out (biological repicates).

2014-09-30 | E-GEOD-61721 | biostudies-arrayexpress

Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER [HMLER]

2014-09-30 | GSE61721 | GEO

Integrated analysis of microRNA and mRNA expression and association with HIF binding in MCF-7 cells under hypoxia [miRNA]

Project description:Purpose: We aimed to investigate in depth the regulation of microRNA expression by hypoxia in the breast cancer cell line MCF-7, establish the relationship between microRNA expression and HIF binding sites, pri-miRNA transcription and microRNA processing gene expression. Methods: microRNA sequencing data and gene expression microarray data were generated from MCF-7 cells submitted to an hypoxia timecourse (16h, 32h and 48h at 1% Oxygen). Data was integrated to 500 published high-stringency HIF binding sites identified in MCF-7 cells. Results: We identified 41 microRNAs significantly up- and 28 down- regulated, of which 38 mature and 20 star forms are reported in conjunction with hypoxia for the first time. HIF-1M-NM-1 and HIF-2M-NM-1 binding sites within 50kb distance of microRNA loci were found by integration of HIF ChIP-seq data, showing overall association between binding sites and up-regulation. Gene expression profiling analysis showed no full coordination between pri-miRNA and microRNA expression, pointing towards additional levels of regulation. Several transcripts playing a role in microRNA processing were found regulated by hypoxia, of which two were HIF dependent. Conclusions: The data support the hypothesis that microRNA expression under hypoxia is regulated at transcriptional and post-transcriptional level. HIF is involved at both levels, regulating the transcription of certain microRNAs and also the expression of key elements of the microRNA processing pathway. MicroRNA expression profiles of MCF-7 exposed to hypoxia (1% Oxygen) for 16h (2 replicates), 32h (3 replicates) and 48h (3 replicates) and to normoxia (3 replicates) were generated using Agilent miRNA microarrays. This data was used to validate the microRNA-seq data included in this study.

2014-02-13 | E-GEOD-47532 | biostudies-arrayexpress

Integrated analysis of microRNA and mRNA expression and association with HIF binding in MCF-7 cells under hypoxia (miRNA-Seq)

Project description:Purpose: We aimed to investigate in depth the regulation of microRNA expression by hypoxia in the breast cancer cell line MCF-7, establish the relationship between microRNA expression and HIF binding sites, pri-miRNA transcription and microRNA processing gene expression. Methods: microRNA sequencing data and gene expression microarray data were generated from MCF-7 cells submitted to an hypoxia timecourse (16h, 32h and 48h at 1% Oxygen). Data was integrated to 500 published high-stringency HIF binding sites identified in MCF-7 cells. Results: We identified 41 microRNAs significantly up- and 28 down- regulated, of which 38 mature and 20 star forms are reported in conjunction with hypoxia for the first time. HIF-1M-NM-1 and HIF-2M-NM-1 binding sites within 50kb distance of microRNA loci were found by integration of HIF ChIP-seq data, showing overall association between binding sites and up-regulation. Gene expression profiling analysis showed no full coordination between pri-miRNA and microRNA expression, pointing towards additional levels of regulation. Several transcripts playing a role in microRNA processing were found regulated by hypoxia, of which two were HIF dependent. Conclusions: The data support the hypothesis that microRNA expression under hypoxia is regulated at transcriptional and post-transcriptional level. HIF is involved at both levels, regulating the transcription of certain microRNAs and also the expression of key elements of the microRNA processing pathway. microRNA-seq profiles of MCF-7 exposed to hypoxia (1% Oxygen) for 16h (2 replicates), 32h (2 replicates) and 48h (2 replicates) and to normoxia (2 replicates) were generated using Illumina sequencing platform.

2014-02-13 | E-GEOD-47602 | biostudies-arrayexpress

Integrated analysis of microRNA and mRNA expression and association with HIF binding in MCF-7 cells under hypoxia [mRNA]

Project description:Purpose: We aimed to investigate in depth the regulation of microRNA expression by hypoxia in the breast cancer cell line MCF-7, establish the relationship between microRNA expression and HIF binding sites, pri-miRNA transcription and microRNA processing gene expression. Methods: microRNA sequencing data and gene expression microarray data were generated from MCF-7 cells submitted to an hypoxia timecourse (16h, 32h and 48h at 1% Oxygen). Data was integrated to 500 published high-stringency HIF binding sites identified in MCF-7 cells. Results: We identified 41 microRNAs significantly up- and 28 down- regulated, of which 38 mature and 20 star forms are reported in conjunction with hypoxia for the first time. HIF-1? and HIF-2? binding sites within 50kb distance of microRNA loci were found by integration of HIF ChIP-seq data, showing overall association between binding sites and up-regulation. Gene expression profiling analysis showed no full coordination between pri-miRNA and microRNA expression, pointing towards additional levels of regulation. Several transcripts playing a role in microRNA processing were found regulated by hypoxia, of which two were HIF dependent. Conclusions: The data support the hypothesis that microRNA expression under hypoxia is regulated at transcriptional and post-transcriptional level. HIF is involved at both levels, regulating the transcription of certain microRNAs and also the expression of key elements of the microRNA processing pathway. Gene expression profiles of MCF-7 exposed to hypoxia (1% Oxygen) for 16h (3 replicates), 32h (3 replicates) and 48h (3 replicates) and to normoxia (3 replicates) were generated using Illumina microarrays.

2014-02-13 | E-GEOD-47533 | biostudies-arrayexpress

B-catenin downregulates Dicer to promote ovarian cancer metastasis

Project description:Ovarian cancer is a nearly uniform lethal disease and its highly aggressive metastatic phenotype portends a poor prognosis. Lack of a well-controlled, relevant experimental model has been a major obstacle to identifying key molecules causing metastasis. Here we describe the creation of a new isogenic model of spontaneous human ovarian cancer metastasis exhibiting opposite phenotypes - highly metastatic (HM) and non-metastatic (NM) - both in vitro and in vivo. HM was unique in its ability to metastasize consistently to the peritoneum, mimicking the major dissemination route of human ovarian cancer. In contrast, NM failed to form detectable metastases although it was equally tumorigenic. Using comparative label-free quantitative LC-MS/MS, we identified b-catenin which we demonstrated for the first time a direct role in the pathogenesis of ovarian cancer metastasis. Our studies also revealed a previously unrecognized role of b-catenin in the downregulation of multiple microRNAs (miRNAs) through attenuating miRNA biogenesis by targeting Dicer, a key component of the microRNA processing machinery. One such downregulated miRNAs was miR-29s involved in epithelial-to-mesenchymal transition and subsequent stem cell traits. Silencing b-catenin or overexpressing Dicer or miR-29 mimics in HM significantly reduced the ability of these cells to migrate. B-catenin knockdown cells also failed to metastasize in an orthotopic model of ovarian cancer. Meta-analysis revealed an increase in CTNNB1 and a decrease in DICER1 expression levels in the high-risk group. These results uncover b-catenin as a critical player in promoting ovarian cancer aggressiveness and a new mechanism linking between b-catenin and miRNA downregulation underlying this process.

2017-07-03 | PXD006327 | Pride

miRNA expression data in MCF-7 breast cancer Cell line post BCAS2 and FST knockdown

Project description:Previously, we have confirmed the tumor suppressive role of Estrogen Related Receptor β (ERRβ) in breast cancer by modulation of ER transcriptional activities on Breast Cancer Amplified Sequence 2 (BCAS2) and Follistatin(FST).In the mentioned study, we proved downregulation of Cyclin D1 by BCAS2.In the previous report, we have also proved downregulation of FST by BCAS2 through inhibition of β-catenin/TCF-4 complex recruitment on FST promoter. Interestingly, Cyclin D1 induction by FST has been also reported by a different group.Recently, Cyclin D1 expression has been found to be associated with DICER1 induction. Hence it may be speculated, that a part of miRNA population, which involves Dicer for processing, is regulated by BCAS2. And it is also possible, that FST may oppose the effect of BCAS2 on those Dicer-processed miRNAs.This Dicer-regulation by Cyclin D1was reported in Luminal A type of breast cancer. Hence, we chose MCF-7 breast cancer cells for miRNA profiling post knocking down BCAS2 and FST.

2017-10-31 | GSE89390 | GEO

Project description:Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER

| PRJNA261952 | ENA

Breast Cancer Cell Secretome Analysis to Decipher miRNA Tumor Biology and Discover Potential Biomarkers

Project description:MicroRNA (miRNA/miR) miR526b and miR655 overexpressed tumor cell-free secretions promote breast cancer phenotypes in the tumor microenvironment (TME). However, the mechanisms of miRNA regulating TME have never been investigated. With mass spectrometry analysis of MCF7-miRNA-overexpressed versus miRNA-low MCF7-Mock tumor cell secretomes, we identified 34 novel secretory proteins coded by eight genes YWHAB, TXNDC12, MYL6B, SFN, FN1, PSMB6, PRDX4, and PEA15 those are differentially regulated. We used bioinformatic tools and systems biology approaches to identify these markers’ role in breast cancer. Gene ontology analysis showed that the top functions are related to apoptosis, oxidative stress, membrane transport, and motility, supporting miRNA-induced phenotypes. These secretory markers expression is high in breast tumors, and a strong positive correlation exists between upregulated markers’ mRNA expressions with miRNA cluster expression in luminal A breast tumors. Gene expression of secretome markers is higher in tumor tissues compared to normal samples, and immunohistochemistry data supported gene expression data. Moreover, both up and downregulated marker expressions are associated with breast cancer patient survival. miRNA regulates these marker protein expressions by targeting transcription factors of these genes. Premature miRNA (pri-miR526b and pri-miR655) are established breast cancer blood biomarkers. Here we report novel secretory markers upregulated by miR526b and miR655 (YWHAB, MYL6B, PSMB6, and PEA15) are significantly upregulated in breast cancer patients’ plasma, and are potential breast cancer biomarkers.

2023-05-10 | PXD031771 | Pride

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