scholarly journals A partially disordered region connects gene repression and activation functions of EZH2

2020 ◽  
Vol 117 (29) ◽  
pp. 16992-17002 ◽  
Author(s):  
Lianying Jiao ◽  
Murtada Shubbar ◽  
Xin Yang ◽  
Qi Zhang ◽  
Siming Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Gene Activation ◽  
Activation Function ◽  
Binary Complex ◽  
Protein Oligomerization ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Transcriptional Coactivator ◽  
H3k27 Methylation

Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethylation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene repressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcription machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2−EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is entirely sequestered. The EZH2 TAD can be unlocked by cancer-specific EZH2 phosphorylation events to undergo structural transitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The corresponding TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural context of the EZH2 TAD.

scholarly journals Gene Expression and Transcriptome Profiling of Changes in a Cancer Cell Line Post-Exposure to Cadmium Telluride Quantum Dots: Possible Implications in Oncogenesis

Dose-Response ◽  
2021 ◽  
Vol 19 (2) ◽  
pp. 155932582110198
Author(s):  
Mohammed S. Aldughaim ◽  
Mashael R. Al-Anazi ◽  
Marie Fe F. Bohol ◽  
Dilek Colak ◽  
Hani Alothaid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantum Dots ◽  
Cancer Cells ◽  
Cadmium Telluride ◽  
Cancer Progression ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dependent Manner ◽  
Cdte Qds ◽  
Cadmium Telluride Quantum Dots

Cadmium telluride quantum dots (CdTe-QDs) are acquiring great interest in terms of their applications in biomedical sciences. Despite earlier sporadic studies on possible oncogenic roles and anticancer properties of CdTe-QDs, there is limited information regarding the oncogenic potential of CdTe-QDs in cancer progression. Here, we investigated the oncogenic effects of CdTe-QDs on the gene expression profiles of Chang cancer cells. Chang cancer cells were treated with 2 different doses of CdTe-QDs (10 and 25 μg/ml) at different time intervals (6, 12, and 24 h). Functional annotations helped identify the gene expression profile in terms of its biological process, canonical pathways, and gene interaction networks activated. It was found that the gene expression profiles varied in a time and dose-dependent manner. Validation of transcriptional changes of several genes through quantitative PCR showed that several genes upregulated by CdTe-QD exposure were somewhat linked with oncogenesis. CdTe-QD-triggered functional pathways that appear to associate with gene expression, cell proliferation, migration, adhesion, cell-cycle progression, signal transduction, and metabolism. Overall, CdTe-QD exposure led to changes in the gene expression profiles of the Chang cancer cells, highlighting that this nanoparticle can further drive oncogenesis and cancer progression, a finding that indicates the merit of immediate in vivo investigation.

scholarly journals SLC26A2 gene expression levels in melanoma

2021 ◽  
Vol 31 (Supplement_2) ◽  
Author(s):  
Diana Assis ◽  
Ana Luísa De Sousa-Coelho
Keyword(s):  
Gene Expression ◽  
Cancer Cells ◽  
Normal Skin ◽  
Braf Inhibitor ◽  
Ovarian Cancer Cells ◽  
Data Sets ◽  
Dependent Manner ◽  
Therapeutic Decisions ◽  
Pharmacological Screening ◽  
And Function

Abstract Background A recent repurposing pharmacological screening revealed that vanadium-containing drugs anti-proliferative action in ovarian cancer cells was SLC26A2-dependent. SLC26A2/DTDST is a sulfate transporter, related to chondrodysplasia syndromes. Despite some reports on colon cancer, there are no studies on SLC26A2 performed in melanoma in the literature. Methods To better understand its potential use as biomarker for therapeutic decisions in melanoma, we performed gene expression analyses of the data available at GEO profiles (NCBI). Gene data sets that allowed analysis of SLC26A2 expression (1) in melanoma; (2) in response to drugs; (3) regulated by other proteins, were selected. Results Our results showed that, compared to normal skin or benign nevi, SLC26A2 expression was 2.5-fold higher in malignant melanoma (P = 0.019). Compared to the primary tumor, SLC26A2 expression tripled in melanoma (P = 0.022). We found a 6% decrease of SLC26A2 expression in A375 melanoma cells treated with BRAF inhibitor Vemurafenib (P < 0.001). After treatment of A375 cells with MLN4924, a selective inhibitor of the activating enzyme of Nedd8, SLC26A2 decreased in a time-dependent manner ( > 80% at 24 h; P < 0.001). In Sk-Mel-2 cells overexpressing E2F-1, a transcription factor that induces apoptosis in cancer cells, SLC26A2 levels were reduced by 76.4% (P = 0.067). In A375P cells depleted of PGC1α, an important metabolic co-activator in mitochondrial biogenesis and function, SLC26A2 levels increased 16% (P = 0.013). Conclusions From this work, we unveiled, for the first time, potential clues to better understand the regulation and role of SLC26A2 in melanoma. Though, it is still to be determined whether SLC26A2 is a driver or a passenger in the disease.

scholarly journals Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4709 ◽  
Author(s):  
Seong-Hun Kim ◽  
Hua Jin ◽  
Ruo Yu Meng ◽  
Da-Yeah Kim ◽  
Yu Chuan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Cancer Cells ◽  
Ursolic Acid ◽  
Hippo Pathway ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Protein Levels ◽  
Tumor Tissues ◽  
The Hippo Pathway

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family (RASSF1), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

scholarly journals GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors.

1997 ◽  
Vol 17 (5) ◽  
pp. 2735-2744 ◽  
Author(s):  
H Hong ◽  
K Kohli ◽  
M J Garabedian ◽  
M R Stallcup
Keyword(s):  
Vitamin D ◽  
Glucocorticoid Receptor ◽  
Nuclear Receptors ◽  
Steroid Hormone Receptors ◽  
Yeast Cells ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Transcriptional Coactivator ◽  
Vitamin D Receptors ◽  
Receptor Alpha

After binding to enhancer elements, transcription factors require transcriptional coactivator proteins to mediate their stimulation of transcription initiation. A search for possible coactivators for steroid hormone receptors resulted in identification of glucocorticoid receptor interacting protein 1 (GRIP1). The complete coding sequence for GRIP1, isolated from a mouse brain cDNA library, contains an open reading frame of 1,462 codons. GRIP1 is the probable ortholog of the subsequently identified human protein transcription intermediary factor 2 (TIF2) and is also partially homologous to steroid receptor coactivator 1 (SRC-1). The full-length GRIP1 interacted with the hormone binding domains (HBDs) of all five steroid receptors in a hormone-dependent manner and also with HBDs of class II nuclear receptors, including thyroid receptor alpha, vitamin D receptor, retinoic acid receptor alpha, and retinoid X receptor alpha. In contrast to agonists, glucocorticoid antagonists did not promote interaction between the glucocorticoid receptor and GRIP1. In yeast cells, GRIP1 dramatically enhanced the transcriptional activation function of proteins containing the HBDs of any of the above-named receptors fused to the GAL4 DNA binding domain and thus served as a transcriptional coactivator for them. This finding contrasts with previous reports of TIF2 and SRC-1, which in mammalian cells enhanced the transactivation activities of only a subset of the steroid and nuclear receptors that they physically interacted with. GRIP1 also enhanced the hormone-dependent transactivation activity of intact glucocorticoid receptor, estrogen receptor, and mineralocorticoid receptor. Experiments with glucocorticoid receptor truncation and point mutants indicated that GRIP1 interacted with and enhanced the activity of the C-terminal AF-2 but not the N-terminal AF-1 transactivation domain of the glucocorticoid receptor. These results demonstrate directly that AF-1 and AF-2 domains accomplish their transactivation activities through different mechanisms: AF-2 requires GRIP1 as a coactivator, but AF-1 does not.

HIF-1 Supports the Survival of Multiple Myeloma Cells through the Induction of Survivin Gene.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 110-110 ◽  
Author(s):  
Keita Kirito ◽  
Hu Yongzhen ◽  
Kozue Yoshida ◽  
Toru Mitsumori ◽  
Kei Nakajima ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Dependent Manner ◽  
Survivin Mrna ◽  
Myeloma Cells ◽  
Survivin Gene ◽  
Growth And Survival ◽  
Induced Apoptosis

Abstract In spite of the recent development of therapeutic strategies, multiple myeloma (MM) still remains incurable. Several cytokines and chemokines contribute to progression of the disease and acquisition of resistance to chemotherapy. These humoral factors support the growth and survival of myeloma cells through the regulation of transcription factors including NF-κB, Stat3 and FOXO3a. Hypoxia inducible factor-1 (HIF-1) is an important transcription factor that is activated under low oxygen tension and controls dozens of genes involved in angiogenesis, energy production and resistance to apoptosis. Interestingly, HIF-1 is frequently activated in cancer cells even under normoxic condition and it is well established that HIF-1 expression and activation correlates with tumor progression and resistance to cancer treatments. In this study, we investigated whether HIF-1 is involved in the biology of multiple myeloma. To this end, we used three MM cell lines U266, RPMI8226 and KMM-1. After informed consent, we also prepared primary MM cells from bone marrow samples of patients (n=5) using anti-CD138 magnetic beads. Initially, we treated MM cells with insulin-like growth factor-1 (IGF-1) and IL-6, both of which are major growth and survival factors for myeloma cells. Treatment with IGF-1 and, to be a lesser degree, IL-6 clearly enhanced expression of HIF-1α, a subunit of HIF-1, in all three cell lines. Similar results were obtained from isolated primary MM cells. Based on several lines of evidence that survivin, a member of inhibitor of apoptosis (IAP) family protein, is transcriptionally regulated by HIF-1 in breast cancer cells, and that this anti-apoptotic factor is important for growth of MM cells, we examined whether HIF-1 supports the survival of MM cells through the induction of survivin. Quantitative RT-PCR assay revealed that IGF-1 increased survivin mRNA both in MM cell lines and in primary MM cells. In addition, IGF-1 activated survivin gene promoter containing a HIF-1-binding site. To confirm that IGF-1-induced activation of survivin gene is mediated by HIF-1, we treated MM cell lines with echinomycin, an inhibitor of DNA-binding activity of HIF-1. As expected, echinomycin inhibited IGF-1-induced survivin gene expression in a dose-dependent manner. The inhibitor also induced apoptosis of MM cells, and IGF-1 could not rescue the MM cells from echinomycin-induced apoptosis. Furthermore, echinomycin enhanced melphalan-induced apoptosis of MM cells. To further examine the involvement of HIF-1 in IGF-1-induced survivin gene expression, we generated three independent HIF-1α knockdown KMM-1 clones using siRNA system. Survivin mRNA was not detected in the HIF-1α knockdown cells, and these clones easily underwent apoptosis even in the presence of IGF-1, compared to the parental cells. Taken together, HIF-1 plays a pivotal role in survival of MM cells through the induction of survivin gene. In conclusion, HIF-1 might be an attractive therapeutic target for MM.

scholarly journals A copper switch for inducing CRISPR/Cas9-based transcriptional activation tightly regulates gene expression in Nicotiana benthamiana.

2021 ◽  
Author(s):  
Elena Garcia-Perez ◽  
Borja Diego-Martin ◽  
Alfredo Quijano-Rubio ◽  
Elena Moreno Gimenez ◽  
Diego Orzaez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Nicotiana Benthamiana ◽  
Gene Networks ◽  
Rna Binding ◽  
Gene Activation ◽  
Dependent Manner ◽  
Copper Binding ◽  
Control Of Gene Expression ◽  
Guide Rna

CRISPR-based programmable transcriptional activators (PTAs) are used in plants for rewiring gene networks. Better tuning of their activity in a time and dose-dependent manner should allow precise control of gene expression. Here, we report the optimization of a Copper Inducible system called CI-switch for conditional gene activation in Nicotiana benthamiana. In the presence of copper, the copper-responsive factor CUP2 undergoes a conformational change and binds a DNA motif named copper-binding site (CBS). In this study, we tested several activation domains fused to CUP2 and found that the non-viral Gal4 domain results in strong activation of a reporter gene equipped with a minimal promoter, offering advantages over previous designs. To connect copper regulation with downstream programable elements, several copper-dependent configurations of the strong dCasEV2.1 PTA were assayed, aiming at maximizing activation range, while minimizing undesired background expression. The best configuration involved a dual copper regulation of the two protein components of the PTA, namely dCas9:EDLL and MS2:VPR, and a constitutive RNA pol III-driven expression of the third component, a guide RNA with anchoring sites for the MS2 RNA-binding domain. With these optimizations in place, the CI/dCasEV2.1 system resulted in copper-dependent activation rates of 2,600-fold for the endogenous N. benthamiana DFR gene, with negligible expression in the absence of the trigger. The tight regulation of copper over CI/dCasEV2.1 makes this system ideal for the conditional production of plant-derived metabolites and recombinant proteins in the field.

The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma

2019 ◽  
Vol 19 (3) ◽  
pp. 140-146
Author(s):  
Bin Zheng ◽  
QingYun Mai ◽  
JinXing Jiang ◽  
QinQin Zhou
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Gene Activation ◽  
Specific Gene ◽  
Dependent Manner ◽  
Master Regulators ◽  
High Incidence ◽  
Underlying Mechanisms

Small double-strand RNAs have been recognized as master regulators of gene expression. In contrast to the evolutionary conserved RNA interference machinery, which degrades or inhibits the translation of target mRNAs, small activating RNA (saRNA) activates the specific gene in a target dependent manner through a similar mechanism as RNAi. Recently, saRNA mediated expression regulation of specific genes has been extensively studied in cancer researches. Of particular interest is the application of the RNA mediated gene activation within colorectal cancer (CRC) development, due to the high incidence of the CRC. In this review, we summarize the current knowledge of saRNA mediated genetic activation and its underlying mechanisms. Furthermore, we highlight the advantages of the utilization of saRNAs induced gene expression as an investigating tool in colorectal cancer research. Finally, the possibility and the challenge of the saRNA application as a potential therapy for colorectal cancer are addressed.

Possible Selective Cytotoxicity of Vanadium Complex on Breast Cancer Cells Involving Pathophysiological Pathways

2020 ◽  
Vol 19 (17) ◽  
pp. 2130-2139 ◽  
Author(s):  
Eman S. El-Shafey ◽  
Eslam S. Elsherbiny
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Caspase 3 ◽  
Therapeutic Agent ◽  
Notch Pathway ◽  
Vanadium Complex ◽  
Dependent Manner

Background: Triple-Negative Breast Cancers (TNBC) are among the most aggressive and therapyresistant breast tumors. Development of new treatment strategies that target pathways involved in cancer cells resistance is an attractive candidate to overcome therapeutic resistance. Objective: To clarify the antitumor activity of [VO (bpy)2 Cl] Cl complex as a new therapeutic agent through studying the interplay between apoptosis, autophagy and notch signaling pathways. Methods: Proliferation of MDA-MB-231 cells and IC50 value of the vanadium complex were assessed by MTT assay. Flow cytometry was utilized to detect cell cycle distribution, apoptosis assay, LC3 levels and Acid Vascular Organelles (AVOs). Caspase 3 levels were detected by ELISA. Changes in Notch1 gene expression were assessed by real-time PCR. AVOs qualitative detection was assessed by a fluorescence microscope. Results: The growth of MDA-MB-231 cells was suppressed after treatment with [VO (bpy)2 Cl] Cl complex, in a dose-dependent manner. The affinity for apoptotic cell death induction was shown through the increase in the sub G0 peak, the percentage of early and late apoptotic phases, and the elevation in caspase 3 levels. The affinity for autophagic cell death induction was observed through the increase in the G0/G1 phase, G2/M arrest, the increase of AVOs red fluorescence and elevated LC3 levels. The affinity for notch pathway inhibition was shown through the suppression of Notch 1 gene expression. Conclusion: [VO (bpy)2 Cl] Cl complex could be a promising candidate as therapeutic agent targeting different therapeutic targets including apoptosis, autophagy and notch signaling pathways.

scholarly journals Recruitment of the SWI-SNF Chromatin Remodeling Complex as a Mechanism of Gene Activation by the Glucocorticoid Receptor τ1 Activation Domain

2000 ◽  
Vol 20 (6) ◽  
pp. 2004-2013 ◽  
Author(s):  
Annika E. Wallberg ◽  
Kristen E. Neely ◽  
Ahmed H. Hassan ◽  
Jan-Åke Gustafsson ◽  
Jerry L. Workman ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Mammalian Cells ◽  
Gene Activation ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Chromatin Remodeling Complex ◽  
Nucleosomal Dna ◽  
Target Promoters

ABSTRACT The SWI-SNF complex has been shown to alter nucleosome conformation in an ATP-dependent manner, leading to increased accessibility of nucleosomal DNA to transcription factors. In this study, we show that the SWI-SNF complex can potentiate the activity of the glucocorticoid receptor (GR) through the N-terminal transactivation domain, τ1, in both yeast and mammalian cells. GR-τ1 can directly interact with purified SWI-SNF complex, and mutations in τ1 that affect the transactivation activity in vivo also directly affect τ1 interaction with SWI-SNF. Furthermore, the SWI-SNF complex can stimulate τ1-driven transcription from chromatin templates in vitro. Taken together, these results support a model in which the GR can directly recruit the SWI-SNF complex to target promoters during glucocorticoid-dependent gene activation. We also provide evidence that the SWI-SNF and SAGA complexes represent independent pathways of τ1-mediated activation but play overlapping roles that are able to compensate for one another under some conditions.

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