scholarly journals Chromatin topology defines estradiol-primed progesterone receptor and PAX2 binding in endometrial cancer cells

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Alejandro La Greca ◽  
Nicolás Bellora ◽  
François Le Dily ◽  
Rodrigo Jara ◽  
Ana Silvina Nacht ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Fine Tuning ◽  
Open Chromatin ◽  
Altered Expression ◽  
Endometrial Tumor ◽  
Long Range Interactions ◽  
Specific Receptors ◽  
Endometrial Carcinomas

Estrogen (E2) and Progesterone (Pg), via their specific receptors (ERalpha and PR), are major determinants in the development and progression of endometrial carcinomas, However, their precise mechanism of action and the role of other transcription factors involved are not entirely clear. Using Ishikawa endometrial cancer cells, we report that E2 treatment exposes a set of progestin-dependent PR binding sites which include both E2 and progestin target genes. ChIP-seq results from hormone-treated cells revealed a non-random distribution of PAX2 binding in the vicinity of these estrogen-promoted PR sites. Altered expression of hormone regulated genes in PAX2 knockdown cells suggests a role for PAX2 in fine-tuning ERalpha and PR interplay in transcriptional regulation. Analysis of long-range interactions by Hi-C coupled with ATAC-seq data showed that these regions, that we call 'progestin control regions' (PgCRs), exhibited an open chromatin state even before hormone exposure and were non-randomly associated with regulated genes. Nearly 20% of genes potentially influenced by PgCRs were found to be altered during progression of endometrial cancer. Our findings suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with PAX2 to accessible chromatin regions. What maintains these regions open remains to be studied.

scholarly journals Higher-order chromatin organization defines Progesterone Receptor and PAX2 binding to regulate estradiol-primed endometrial cancer gene expression

2019 ◽  
Author(s):  
Alejandro La Greca ◽  
Nicolás Bellora ◽  
Francois Le Dily ◽  
Rodrigo Jara ◽  
Javier Quilez Oliete ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endometrial Cancer ◽  
Binding Sites ◽  
Specific Binding ◽  
Open Chromatin ◽  
Cancer Gene ◽  
Specific Binding Sites ◽  
Endometrial Tumor ◽  
Long Range Interactions ◽  
Specific Receptors

AbstractEstrogen (E2) and Progesterone (Pg), via their specific receptors (ER and PR respectively), are major determinants in the development and progression of endometrial malignancies. Here, we have studied how E2 and the synthetic progestin R5020 affect genomic functions in Ishikawa endometrial cancer cells. Using ChIPseq in cells exposed to the corresponding hormones, we identified cell specific binding sites for ER (ERbs) and PR (PRbs), which mostly correspond to independent sites but both adjacent to sites bound by PAX2. Analysis of long-range interactions by Hi-C showed enrichment of regions co-bound by PR and PAX2 inside TADs that contain differentially progestin-regulated genes. These regions, which we call “progestin control regions” (PgCRs), exhibit an open chromatin state prior to the exposure to the hormone. Our observations suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with partner transcription factors to PgCRs, compartmentalizing hormone-independent open chromatin.

scholarly journals Pervasive promoter hypermethylation of silenced TERT alleles in human cancers

2020 ◽  
Vol 43 (5) ◽  
pp. 847-861 ◽  
Author(s):  
David Esopi ◽  
Mindy Kim Graham ◽  
Jacqueline A. Brosnan-Cashman ◽  
Jennifer Meyers ◽  
Ajay Vaghasia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Transcriptional Repression ◽  
Cpg Island ◽  
Promoter Hypermethylation ◽  
Fine Tuning ◽  
Open Chromatin ◽  
Promoter Mutations

Abstract Background In cancers, maintenance of telomeres often occurs through activation of the catalytic subunit of telomerase, encoded by TERT. Yet, most cancers show only modest levels of TERT gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T). The role of epigenetic mechanisms, including DNA methylation, in regulating TERT gene expression in cancer cells is as yet not fully understood. Methods Here, we have carried out the most comprehensive characterization to date of TERT promoter methylation using ultra-deep bisulfite sequencing spanning the CpG island surrounding the core TERT promoter in 96 different human cell lines, including primary, immortalized and cancer cell types, as well as in control and reference samples. Results In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent C228T and C250T TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. However, at the allele-level, we generally found that hypermethylation of promoter sequences in cancer cells is associated with repressed expression, and the remaining unmethylated alleles marked with open chromatin are largely responsible for the observed TERT expression in cancer cells. Conclusions Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to attenuation of TERT activation in cancer cells. This type of fine tuning of TERT expression may account for the modest activation of TERT expression in most cancers.

scholarly journals Effect of microRNA-29b on proliferation, migration, and invasion of endometrial cancer cells

2019 ◽  
Vol 47 (8) ◽  
pp. 3803-3817
Author(s):  
Jian Kong ◽  
Xiuting He ◽  
Yan Wang ◽  
Jie Li
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Water Soluble ◽  
Migration And Invasion ◽  
Chemotherapy Response ◽  
Aberrant Expression ◽  
Altered Expression ◽  
Matrigel Invasion ◽  
Tensin Homolog ◽  
Induced Apoptosis

Objective Aberrant expression of microRNAs is a key regulator of tumorigenesis and progression in endometrial cancer. We assessed the effect of microRNA-29b (miR-29b) on proliferation, chemosensitivity, migration, and invasion of endometrial cancer cells. Methods The proliferation of endometrial cancer cells was examined by water-soluble tetrazolium (WST)-1 assay. The effects of miR-29b on migration and invasion were evaluated by transwell migration and Matrigel invasion assays. Western blotting was used to assess protein expression levels after altered expression of miR-29b. The effect of miR-29b on cisplatin-induced apoptosis was examined by Caspase-Glo 3/7 assay. Results miR-29b inhibited proliferation and decreased migration and invasion of endometrial cancer cells. It also enhanced the sensitivity of endometrial cancer cells to cisplatin and increased cisplatin-induced apoptosis by regulating expression of BAX and Bcl-2. Moreover, miR-29b changed the expression level of phosphatase and tensin homolog (PTEN) and p-AKT by directly binding to the 3′ untranslated region of PTEN. Conclusion miR-29b played important roles in proliferation and progression in endometrial cancer cells by direct regulation of PTEN. It might be used as a biomarker to predict chemotherapy response and prognosis in endometrial cancer.

MicroRNA-mutant P53 crosstalk in chemoresistance: a hint to monitor therapy outcome

MicroRNA ◽  
2020 ◽  
Vol 09 ◽  
Author(s):  
Andrea Speciale ◽  
Paola Monti ◽  
Gilberto Fronza ◽  
Alberto Izzotti ◽  
Paola Menichini
Keyword(s):  
Cell Cycle ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Target Genes ◽  
Therapy Outcome ◽  
In Vivo Studies ◽  
Mutant P53 ◽  
Altered Expression ◽  
Monitoring Therapy

: The chemoresistance of cancer cells is a multifactorial mechanism, in which de-regulated apoptotic pathways, the oxidative response and cancer cell migration play a crucial role. A key player in the control of such pathways is the tumor suppressor gene TP53, also defined as the “guardian of the genome”, encoding the P53 tetrameric transcription factor. P53, following cell injuries, can activate the transcription of several target genes crucial for the induction of apoptosis, cell cycle arrest, modulation of senescence, DNA repair, autophagy and metabolism. Importantly, TP53 gene is mutated in nearly 50% of human cancers, implying an altered expression of target genes in cancer cells. The presence of TP53 mutations can also affect the expression of several small non-coding RNAs (microRNAs or miRNAs), involved in the same regulation of the apoptotic signaling, cell cycle regulation and cell migration. In mutant P53 expressing tumors, some miRNAs resulted to be down-regulated, while others appeared to be up-regulated as demonstrated by in vitro and in vivo studies. Thus, the expression level of specific P53 responsive miRNAs could be used as a marker of cancer progression and therapy performance. In the present review, we will summarize the role of P53-related miRNAs and their clinical relevance in monitoring therapy outcome and progression of cancers with mutant P53.

scholarly journals Improving Chromatin-Interaction Prediction Using Single-Cell Open-Chromatin Profiles and Making Insight Into the Cis-Regulatory Landscape of the Human Brain

2021 ◽  
Vol 12 ◽  
Author(s):  
Neetesh Pandey ◽  
Omkar Chandra ◽  
Shreya Mishra ◽  
Vibhor Kumar
Keyword(s):  
Human Brain ◽  
Single Cell ◽  
Long Range ◽  
Target Genes ◽  
Interaction Analysis ◽  
Chromatin Interaction ◽  
Open Chromatin ◽  
Cell Type ◽  
Range Interaction ◽  
Long Range Interactions

Single-cell open-chromatin profiles have the potential to reveal the pattern of chromatin-interaction in a cell type. However, currently available cis-regulatory network prediction methods using single-cell open-chromatin profiles focus more on local chromatin interactions despite the fact that long-range interactions among genomic sites play a significant role in gene regulation. Here, we propose a method that predicts both short and long-range interactions among genomic sites using single-cell open chromatin profiles. Our method, termed as single-cell epigenome based chromatin-interaction analysis (scEChIA) exploits signal imputation and refined L1 regularization. For a few single-cell open-chromatin profiles, scEChIA outperformed other tools even in terms of accuracy of prediction. Using scEChIA, we predicted almost 0.7 million interactions among genomic sites across seven cell types in the human brain. Further analysis revealed cell type for connection between genes and expression quantitative trait locus (eQTL) in the human brain and making insight about target genes of human-accelerated-elements and disease-associated mutations. Our analysis enabled by scEChIA also hints about the possible action of a few transcription factors (TFs), especially through long-range interaction in brain endothelial cells.

scholarly journals Molecular Insights into miRNA-Driven Resistance to 5-Fluorouracil and Oxaliplatin Chemotherapy: miR-23b Modulates the Epithelial–Mesenchymal Transition of Colorectal Cancer Cells

2019 ◽  
Vol 8 (12) ◽  
pp. 2115 ◽  
Author(s):  
Stasė Gasiulė ◽  
Nadezda Dreize ◽  
Algirdas Kaupinis ◽  
Raimundas Ražanskas ◽  
Laurynas Čiupas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Chemotherapy Resistance ◽  
Fine Tuning ◽  
Mesenchymal Transition ◽  
Partial Restoration ◽  
Resistant Cells

Although treatment of colorectal cancer with 5-florouracil and oxaliplatin is widely used, it is frequently followed by a relapse. Therefore, there is an urgent need for profound understanding of chemotherapy resistance mechanisms as well as the profiling of predictive markers for individualized treatment. In this study, we identified the changes in 14 miRNAs in 5-fluouracil and 40 miRNAs in oxaliplatin-resistant cell lines by miRNA sequencing. The decrease in miR-224-5p expression in the 5-fluorouracil-resistant cells correlated with drug insensitivity due to its overexpression-induced drug-dependent apoptosis. On the other hand, the miR-23b/27b/24-1 cluster was overexpressed in oxaliplatin-resistant cells. The knockout of miR-23b led to the partial restoration of oxaliplatin susceptibility, showing the essential role of miR-23b in the development of drug resistance by this cluster. Proteomic analysis identified target genes of miR-23b and showed that endothelial–mesenchymal transition (EMT) was implicated in oxaliplatin insensibility. Data revealed that EMT markers, such as vimentin and SNAI2, were expressed moderately higher in the oxaliplatin-resistant cells and their expression increased further in the less drug-resistant cells, which had miR-23b knockout. This establishes that the balance of EMT contributes to the drug resistance, showing the importance of the miR-23b-mediated fine-tuning of EMT in oxaliplatin-resistant cancer cells.

MicroRNAs and their role in hematological malignant diseases

2012 ◽  
Vol 153 (52) ◽  
pp. 2051-2059 ◽  
Author(s):  
Zsuzsanna Gaál ◽  
Éva Oláh
Keyword(s):  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Cancer Tissue ◽  
Altered Expression ◽  
Diagnosis And Prognosis ◽  
Oncologic Patients ◽  
Different Types ◽  
Non Coding Rnas ◽  
Success Of Treatment ◽  
Posttranscriptional Level

MicroRNAs are a class of small non-coding RNAs regulating gene expression at posttranscriptional level. Their target genes include numerous regulators of cell cycle, cell proliferation as well as apoptosis. Therefore, they are implicated in the initiation and progression of cancer, tissue invasion and metastasis formation as well. MicroRNA profiles supply much information about both the origin and the differentiation state of tumours. MicroRNAs also have a key role during haemopoiesis. An altered expression level of those have often been observed in different types of leukemia. There are successful attempts to apply microRNAs in the diagnosis and prognosis of acute lymphoblastic leukemia and acute myeloid leukemia. Measurement of the expression levels may help to predict the success of treatment with different kinds of chemotherapeutic drugs. MicroRNAs are also regarded as promising therapeutic targets, and can contribute to a more personalized therapeutic approach in haemato-oncologic patients. Orv. Hetil., 2012, 153, 2051–2059.

Emodin Enhances the Chemosensitivity of Endometrial Cancer by Inhibiting ROS-Mediated Cisplatin-resistance

2018 ◽  
Vol 18 (7) ◽  
pp. 1054-1063 ◽  
Author(s):  
Ning Ding ◽  
Hong Zhang ◽  
Shan Su ◽  
Yumei Ding ◽  
Xiaohui Yu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endometrial Cancer ◽  
Cancer Cells ◽  
Chemotherapeutic Agent ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Endometrial Cancer Cell ◽  
Animal Survival ◽  
Apoptosis Level

Background: Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug-resistance is the primary cause of treatment failure. Objective: Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method: CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results: Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drugresistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion: This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug-resistance genes.

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