Hypoxia promotes stem cell phenotypes and poor prognosis through epigenetic regulation of DICER
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE61722 | GEO | 2014/09/30
SECONDARY ACCESSION(S): PRJNA261952
REPOSITORIES: GEO
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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 tumour 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 tumour stem cell phenotypes that may underlie poor outcome in breast cancer.
| S-EPMC4255228 | biostudies-literature
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.
| S-ECPF-GEOD-61720 | biostudies-other
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).
| S-ECPF-GEOD-61721 | biostudies-other
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-09-30 | E-GEOD-61722 | biostudies-arrayexpress
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
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
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.
2014-09-30 | GSE61721 | GEO
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.
2014-09-30 | GSE61720 | GEO
Project description:Background: Hormonal therapy using progestins, acting through the progesterone receptor (PR), is a well-established method to treat uterine endometrial hyperplasia and carcinoma. Recent population studies indicate that progestin exposure significantly reduces the incidence of ovarian, pancreatic and lung cancers in addition to endometrial cancer in women. This unexpected differentiating function of progestin in organs outside of the reproductive system led us to hypothesize that progestins/PR are protective against cancer development and progression in many tumor types. Methods: The Cancer Genome Atlas, Oncomine and Prognostic Databases were searched to determine the relative expression of PR in tumors from multiple sites, and clinical outcomes linked to PR expression were determined. In addition, mRNA and protein expression were evaluated using real-time PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assay was performed to understand the PR downregulation mechanisms in tumor cells and patient samples. Methylation-specific PCR was conducted to survey the PR methylation status. The Student’s t-test were performed to determine significance. Flow cytometry was used to quantify apoptotic cells. Results: Low PR expression levels were consistently linked to less favorable clinical outcomes in endometrial, pancreatic, ovarian and non-small cell lung cancers. Clinical specimens and cell lines from these cancers demonstrate low levels of PR, and we now report that the mechanism for loss of PR is mediated through epigenetic repression. However, PR silencing can be overcome with epigenetic modulators. Histone deacetylase inhibitor (LBH589) and hypomethylating agent (5-aza-decitabine) restored functional PR expression at both the mRNA and protein levels and promoted marked cell death through induction of apoptosis in the presence of progesterone. Conclusions: Our studies support the possibility that progestin therapy in combination with epigenetic modulators, a concept we term “molecularly enhanced progestin therapy”, is an approach worthy of study for malignancies originating from tissues outside of the reproductive tract.
| S-EPMC7339273 | biostudies-literature
Project description:Gallbladder cancer (GBC) is a common malignant tumor of the biliary tract, which accounts for 80-95% of biliary tumors worldwide, and is the leading cause of biliary malignant tumor-related death. This study identified PSMC2 as a potential regulator in the development of GBC. We showed that PSMC2 expression in GBC tissues is significantly higher than that in normal tissues, while high PSMC2 expression was correlated with more advanced tumor grade and poorer prognosis. The knockdown of PSMC2 in GBC cells induced significant inhibition of cell proliferation, colony formation and cell motility, while the promotion of cell apoptosis. The construction and observation of the mice xenograft model also confirmed the inhibitory effects of PSMC2 knockdown on GBC development. Moreover, our mechanistic study recognized GNG4 as a potential downstream target of PSMC2, knockdown of which could aggravate the tumor suppression induced by PSMC2 knockdown in vitro and in vivo. In conclusion, for the first time, PSMC2 was revealed as a tumor promotor in the development of GBC, which could regulate cell phenotypes of GBC cells through the interaction with GNG4, and maybe a promising therapeutic target in GBC treatment.
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