scholarly journals CircFOXK2 Promotes Tumor Growth and Metastasis of Pancreatic Ductal Adenocarcinoma via Complexing with RNA Binding Proteins and Sponging MiR-942

2019 ◽  
Author(s):  
Chi Hin Wong ◽  
Ut Kei Lou ◽  
Youjia Li ◽  
Stephen Lam Chan ◽  
Joanna Hung-Man Tong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
List Type ◽  
Interacting Proteins ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Regulate Gene Expression ◽  
Regulate Gene

AbstractObjectiveCircular RNA (circRNA) is a novel class of non-coding RNAs that regulate gene expression. However, the role of circRNAs in pancreatic ductal adenocarcinoma (PDAC) is largely unknown.DesignWe performed circRNA sequencing of non-tumor HPDE and PDAC cells. We investigated the functions of circFOXK2 in PDAC by gain-of-function and loss-of-function assays. Bioinformatics analysis, luciferase assay and microRNA pulldown assays were performed to identify circFOXK2 interacting-miRNAs. To further investigate the mechanism, we performed circRNA-pulldown and mass spectrometry to identify circFOXK2-interacting proteins in PDAC.ResultsWe identified 169 differentially expressed circRNAs in PDAC cells. We validated that one of the circRNAs circFOXK2 was significantly up-regulated in PDAC cells and in 63 % of primary tumor (53 out of 84). Gain-of-function and loss-of-function assays demonstrated that circFOXK2 promoted PDAC cell growth, migration and invasion. CircFOXK2 was also involved in cell cycle progression and apoptosis. circFOXK2 functioned as sponge for miR-942, and in turn promoted the expression of miR-942 targets ANK1, GDNF and PAX6. Furthermore, circFOXK2 interacted with 94 proteins, which were involved in cell adhesion and mRNA splicing. Among these circFOXK2-interacting proteins, YBX1 and hnRNPK were validated by RNA immunoprecipitation. Importantly, circFOKX2 interacted with YBX1 and hnRNPK targets NUF2 and PDXK in PDAC cells. Knockdown of circFOXK2 reduced the binding of YBX1 and hnRNPK to NUF2 and PDXK, and in turn decreased their expressions in PDAC cells.ConclusionWe identified that circFOXK2 promoted PDAC cells growth and metastasis. Also, circFOXK2 complexed with YBX1 and hnRNPK to promote the expressions of oncogenic proteins.Significance of this studyWhat is already known on this subject?Differentially expressed circRNAs are involved in carcinogenesis of many cancers.CircRNAs function as microRNA sponges to regulate gene expression.The roles of circRNAs in PDAC progression is largely unknown.What are the new findings?circFOXK2 is upregulated in PDAC primary tumors.circFOXK2 promotes PDAC tumor growth and liver metastasis.circFOXK2 functions as sponges for miR-942 to promote the expressions of oncogenic ANK1, GDNF and PAX6.circFOXK2 complexes with YBX1 and hnRNPK to promote the expressions of oncogenic proteins in PDAC.How might it impact on clinical practice in the foreseeable future?circFOXK2 upregulation in PDAC may function as a novel biomarker for diagnosis.circFOXK2 may be a novel therapeutic target in treating PDAC.

scholarly journals H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

2019 ◽  
Author(s):  
Yichao Cai ◽  
Ying Zhang ◽  
Yan Ping Loh ◽  
Jia Qi Tng ◽  
Mei Chee Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Target Genes ◽  
Gene Repression ◽  
Xenograft Tumor ◽  
Regulate Gene Expression ◽  
Chromatin Interactions ◽  
Genomic Regions ◽  
Xenograft Tumor Growth ◽  
Regulate Gene

AbstractGene repression and silencers are poorly understood. We reasoned that H3K27me3-rich regions (MRRs) of the genome defined from clusters of H3K27me3 peaks may be used to identify silencers that can regulate gene expression via proximity or looping. MRRs were associated with chromatin interactions and interact preferentially with each other. MRR component removal at interaction anchors by CRISPR led to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. The MRR knockout cells also showed changes in phenotype associated with cell identity, and altered xenograft tumor growth. MRR-associated genes and long-range chromatin interactions were susceptible to H3K27me3 depletion. Our results characterized H3K27me3-rich regions and their mechanisms of functioning via looping.

scholarly journals Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2986
Author(s):  
Fabio Raineri ◽  
Sandrine Bourgoin-Voillard ◽  
Mélissande Cossutta ◽  
Damien Habert ◽  
Matteo Ponzo ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mouse Models ◽  
Wnt Pathway ◽  
The Other ◽  
Ductal Adenocarcinoma ◽  
Loss Of Function ◽  
Tumor Vessels ◽  
Pathway Activation

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.

scholarly journals Synaptic Plasticity is Altered by Supraphysiological Levels of Retinoic Acid Acting Nongenomically however Endogenous Retinoic Acid Has Not Been Shown to Control Synaptic Plasticity

2021 ◽  
Author(s):  
Gregg Duester
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Vitamin A ◽  
Granule Cells ◽  
Dorsal Hippocampus ◽  
Active Form ◽  
Loss Of Function ◽  
Regulate Gene Expression ◽  
Regulate Gene

A paper recently published on forebrain cortical synaptic plasticity reports that retinoic acid (RA) induces synaptopodin-dependent metaplasticity in mouse dentate granule cells (Lenz et al., 2021). Retinoic acid (RA) is the active form of vitamin A that functions as a ligand for nuclear RA receptors that directly bind genomic control regions to regulate gene expression (Chambon, 1996; Ghyselinck and Duester, 2019). However, Lenz et al. report that RA functions in a nongenomic fashion to control forebrain cortical synaptic plasticity which modulates synaptic transmission to effectively respond to specific stimuli; specifically, they report that this nongenomic response occurs in the dorsal hippocampus but not ventral hippocampus. They performed RA treatment studies which provided information on how a supraphysiological level of RA effects synaptic plasticity. However, the authors did not perform an RA loss-of-function study to verify that endogenous RA is required for synaptic plasticity.

Abstract 1304: Specific MUC1 isoforms function to regulate gene expression and tumor growth in pancreatic cancer

2012 ◽  
Author(s):  
Paul M. Grandgenett ◽  
Stephanie K. Bunt ◽  
Ashley M. Mohr ◽  
Prakash Radhakrishnan ◽  
Tomofumi Hamada ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Regulate Gene Expression ◽  
Regulate Gene

scholarly journals H3K27me3-rich genomic regions can function as silencers to repress gene expression via chromatin interactions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yichao Cai ◽  
Ying Zhang ◽  
Yan Ping Loh ◽  
Jia Qi Tng ◽  
Mei Chee Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Growth ◽  
Target Genes ◽  
Gene Repression ◽  
Xenograft Tumor ◽  
Regulate Gene Expression ◽  
Chromatin Interactions ◽  
Genomic Regions ◽  
Xenograft Tumor Growth ◽  
Regulate Gene

AbstractThe mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping.

Human cytomegalovirus US3 and UL36-38 immediate-early proteins regulate gene expression.

1992 ◽  
Vol 66 (1) ◽  
pp. 95-105 ◽  
Author(s):  
A M Colberg-Poley ◽  
L D Santomenna ◽  
P P Harlow ◽  
P A Benfield ◽  
D J Tenney
Keyword(s):  
Gene Expression ◽  
Human Cytomegalovirus ◽  
Immediate Early ◽  
Regulate Gene Expression ◽  
Early Proteins ◽  
Immediate Early Proteins ◽  
Regulate Gene

scholarly journals Arabidopsis heat shock transcription factor HSFA7b positively mediates salt stress tolerance by binding to an E-box-like motif to regulate gene expression

2019 ◽  
Vol 70 (19) ◽  
pp. 5355-5374 ◽  
Author(s):  
Dandan Zang ◽  
Jingxin Wang ◽  
Xin Zhang ◽  
Zhujun Liu ◽  
Yucheng Wang
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Heat Shock ◽  
Salt Tolerance ◽  
Stress Responses ◽  
Ion Homeostasis ◽  
Cellulose Synthase ◽  
Regulate Gene Expression ◽  
E Box ◽  
Regulate Gene

Abstract Plant heat shock transcription factors (HSFs) are involved in heat and other abiotic stress responses. However, their functions in salt tolerance are little known. In this study, we characterized the function of a HSF from Arabidopsis, AtHSFA7b, in salt tolerance. AtHSFA7b is a nuclear protein with transactivation activity. ChIP-seq combined with an RNA-seq assay indicated that AtHSFA7b preferentially binds to a novel cis-acting element, termed the E-box-like motif, to regulate gene expression; it also binds to the heat shock element motif. Under salt conditions, AtHSFA7b regulates its target genes to mediate serial physiological changes, including maintaining cellular ion homeostasis, reducing water loss rate, decreasing reactive oxygen species accumulation, and adjusting osmotic potential, which ultimately leads to improved salt tolerance. Additionally, most cellulose synthase-like (CSL) and cellulose synthase (CESA) family genes were inhibited by AtHSFA7b; some of them were randomly selected for salt tolerance characterization, and they were mainly found to negatively modulate salt tolerance. By contrast, some transcription factors (TFs) were induced by AtHSFA7b; among them, we randomly identified six TFs that positively regulate salt tolerance. Thus, AtHSFA7b serves as a transactivator that positively mediates salinity tolerance mainly through binding to the E-box-like motif to regulate gene expression.

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