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Genome-wide expression profiling of CRC cells (SW620) upon TIMELESS loss expression and/or ZEB1 down regulation

ABSTRACT: Colorectal cancer (CRC) is the third most common cancer worldwide. Recent studies pinpointed TIMELESS (TIM) to be crucially involved in replication protection/genomic stability, DNA damage response (DDR) and coordination of mitotic kinase activation with DNA replication termination. Here we present the first direct evidence of a TIM-ZEB1 axis which control key pathological processes in CRC. We found that loss of TIM expression unleashes ZEB1 which triggers epithelial-to-mesenchymal transition program, cell migration/invasion increase and acquirement of stem-like phenotype of CRC cells. Besides, deranged TIM-ZEB1 axis sets off accumulation of DNA damage and delays DNA damage recovery. It is worth noting that the aggressive and genetically unstable ‘CMS4 - colorectal cancer molecular subtype’ matched with low-TIM expressing CRCs and that patients with low-TIM and high-ZEB1 expression have an adverse outcome. Our results support a critical role for TIM-ZEB1 axis derangement and modulation in determining aggressive disease and poor prognosis in CRC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169576 | GEO | 2022/01/17

REPOSITORIES: GEO

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PRL-1 selectively dephosphorylates TIMELESS

Project description:The timing of behavior under natural light-dark conditions is a function of circadian clocks and photic input pathways. Yet a mechanistic understanding of how these pathways collaborate in animals is lacking. Here we demonstrate in Drosophila that the Phosphatase of Regenerating Liver-1 (PRL-1) sets period length and behavioral phase gated by photic signals. PRL-1 knockdown in PDF clock neurons dramatically lengthens circadian period. PRL-1 mutants exhibit allele-specific interactions with the light- and clock-regulated gene timeless (tim). Moreover, we show that PRL-1 promotes TIM accumulation and dephosphorylation. Interestingly, the PRL-1 mutant period lengthening is suppressed in constant light and PRL-1 mutants display a delayed phase under short, but not long, photoperiod conditions. Thus, our studies reveal that PRL-1 dependent dephosphorylation of TIM is a core mechanism of the clock that sets period length and phase in darkness, enabling the behavioral adjustment to changing day-night cycles.

2020-11-11 | PXD020986 | Pride

Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3 [Illumina HumanHT-12 V4.0]

Project description:Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named PINCR (p53-induced noncoding RNA), is induced ~100-fold after DNA damage and exerts a critical prosurvival function in colorectal cancer cells (CRC) in vitro and tumor growth in vivo. Targeted deletion of PINCR in CRC cells significantly impaired G1 arrest and induced hypersensitivity to chemotherapeutic drugs. PINCR regulates the induction of a subset of p53 targets involved in G1 arrest and apoptosis, including BTG2, RRM2B and GPX1. Using a novel RNA pulldown approach that utilized endogenous S1-tagged PINCR, we show that PINCR associates with the promoters of these genes by binding to RNA-binding protein Matrin 3 that, in turn, associates with p53. Our findings uncover a critical prosurvival function of a p53/PINCR/Matrin 3 axis in response to DNA damage in CRC cells.

2017-05-31 | GSE90085 | GEO

Prosurvival long noncoding RNA PINCR regulates a subset of p53 targets in colorectal cancer cells by binding to Matrin 3 [Affymetrix Human Gene 2.0 ST]

2017-05-31 | GSE90084 | GEO

The IGF2BP3-COPS7B axis facilitates mRNA translation to drive colorectal cancer progression

Project description:Many studies have provided valuable information about genomic and transcriptomic changes that occur in colorectal cancer (CRC). However, protein abundance cannot be reliably predicted by DNA alteration or mRNA expression, which can be partially attributed to post-transcriptional and/or translational regulation of gene expression. In this study, we identified increased translational efficiency (TE) as a hallmark of CRC by evaluating the transcriptomic and proteomic features of CRC patients, along with comparative transcriptomic and ribosome-protected mRNA analysis in colon epithelial cells and colon cancer cells. COPS7B was among the key genes that consistently showed both significant TE increase and protein elevation without transcriptional alteration in CRC. IGF2BP3 enhanced the TE of COPS7B mRNA to promote CRC growth and metastasis. COPS7B was found to be a component of the ribo-interactome that interacted with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation. Collectively, this study revealed the proteomic features of CRC and highlighted elevated mRNA translation as a hallmark of CRC. The identification of the IGF2BP3-COPS7B axis underlying the increased protein synthesis rate in CRC provided a promising therapeutic target to treat this aggressive disease.

2023-08-07 | GSE240217 | GEO

p53 C-terminal acetylation modulates apoptotic program

Project description:Advanced colorectal cancer (CRC) is an unresolved clinical problem. Epigenetic drugs belonging to the group of histone deacetylase inhibitors (HDACi) may combat CRC in rationally designed treatment schedules. Unfortunately, there is sparse evidence on molecular mechanisms and markers that determine cellular sensitivity to HDACi. Irinotecan is widely used to treat CRC and causes replication stress (RS) and DNA damage as topoisomerase-I inhibitor. We applied irinotecan and the class I HDACi entinostat (MS-275) to isogenic p53-positive and -negative CRC cells. Combinations of irinotecan and MS-275 evoke mitochondrial damage, caspase-mediated apoptosis, and RS-associated DNA damage synergistically and p53-dependently. Targeted mass spectrometry and immunoblot show that irinotecan induces phosphorylation, acetylation, and accumulation of p53 and its target genes. Addition of MS-275 augments the irinotecan-induced acetylation of C-terminal lysine residues of p53 but decreases its phosphorylation and p53 target gene induction. Furthermore, MS-275 increases the amount of acetylated p53 at mitochondria and dysregulates the expression of pro- and anti-apoptotic BCL2 proteins in irinotecan-treated cells. Regarding DNA repair, we see that MS-275 represses the homologous recombination (HR) filament protein RAD51, which limits DNA damage and pro-apoptotic effects of irinotecan. These data suggest that key class I HDAC-dependent functions of p53 in cells with RS are linked to mitochondrial damage and a breakdown of HR. Most importantly, combinations of irinotecan plus MS-275 also kill short-term primary CRC cell cultures and organoids from CRC patients but spare organoids of adjacent matched normal tissue. Thus, irinotecan/HDACi treatment is a promising new approach for the therapy of p53-proficient tumors with clinically tractable inhibitors.

2022-02-15 | PXD019999 | Pride

Genome-wide characterization of BCL6/STAT5-switch target genes identifies reprogramming of DNA damage response as a novel branch of RAC1/PAK1 signalling

Project description:The RAC1 GTPase and its effector PAK1 have been found to be overexpressed or hyperactivated in colorectal cancer (CRC), one of the most prevalent types of cancer in the world. This overexpression frequently correlates with chemoresistance and less favourable prognoses. We previously showed that the activation of RAC1/PAK1 signalling promotes a switch between the BCL6 transcriptional repressor and the STAT5 transcriptional activator at a subset of pro-proliferative gene promoters. Here we used ChIP-Seq, under conditions of pathway inhibition and stimulation, to identify the BCL6/STAT5-switch binding sites throughout the genome. Using a knowledge-driven pipeline for ChIP-Seq data analysis, we identify 3774 genomic features associated to the switch-motif, with a significant enrichment in protein-coding genes involved in DNA damage repair pathways. Stimulation of RAC1/PAK1 signalling in DLD-1 CRC cells increased the expression of these genes and significantly enhanced DNA repair in response to damage induced by alkylating agents. Our results reveal a new transcriptional reprogramming mechanism whereby the alternate binding of a repressor and an activator protein to low-affinity motifs is used to coordinate a transcriptional response to DNA damage. This mechanism may link the upregulation of the RAC1/PAK1 pathway to the chemoresistant phenotype of aggressive CRCs.

2019-04-30 | GSE97938 | GEO

Gene expression profile for naïve CD4+ T cells after 60-hour-treatment by IL-27

Project description:The inhibitory receptor Tim-3 has emerged as a critical regulator of the T cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signaling pathways that drive Tim-3 expression. Here, we demonstrate that IL-27 induces NFIL3, which promotes permissive chromatin remodeling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signaling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned Th1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumor-infiltrating lymphocytes (TILs) from IL-27R-/- mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumor growth control. Thus, our data identify an IL-27/NFIL3 signaling axis as a key regulator of effector T cell responses via induction of Tim-3, IL-10, and T cell dysfunction. Through gene expression profile analysis, we identified a series of transcription factors that are induced by IL-27. Particularly, the induction of NFIL3 is highly relevant to Tim-3 expression. Naïve CD4+ T cells from C57BL/6 mice were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies for 60 hours. The cells were subjected to gene profile analysis. A comparative transcriptome analysis between cells under neutral culture condition (Untreated) and cells treated with IL-27 (IL-27-treated) was peformed to screen transcription factors that are induced by IL-27 signaling.

2015-01-31 | E-GEOD-63628 | biostudies-arrayexpress

Streptococcus gallolyticus modulates phase I biotransformation enzymes in colorectal cancer cells through the aryl hydrocarbon receptor.

Project description:The opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify S. gallolyticus-induced pathways that could on the long-term add to CRC progression. Transcription profiling of S. gallolyticus-exposed CRC-cells revealed the persistent induction of enzymes involved in biotransformation pathways. Specifically, a diffusible factor of S. gallolyticus (SGF-X) interacts with the aryl hydrocarbon receptor thereby inducing CYP1 enzymes that catalyze the bioactivation of polycyclic aromatic hydrocarbons (PAHs) into toxic intermediates. Importantly, priming CRC-cells with SGF-X containing medium increased the DNA damaging effect of the PAH 3-methylcholanthrene, which was not observed for other intestinal bacteria. In conclusion, this study shows for the first time that bacteria can modulate the biotransformation capacity of CRC-cells that offers a novel theory for a contributing role of S. gallolyticus in the etiology of sporadic CRC. Key words : Colorectal cancer cells, Streptococcus bovis, streptococcus gallolyticus, host-pathogen interactions, Cytochrome P4501A1, DNA-damage, polycyclic aromatic hydrocarbons

2015-06-01 | GSE29295 | GEO

Mast cells elicit protection against colorectal tumors by modulating the immune response during early tumorigenic steps

Project description:Mast cells (MC) alter the development of colorectal cancer (CRC), although their precise role remains poorly defined. Here we show that MC numbers vary in CRC patients, which directly impacts on lymphocytes population. Mouse-based mechanistic experiments reveal that an intricate MC-lymphocyte axis can either promote or inhibit the CRC development, as well as be pharmacologically explored. Therefore, MC activity can be modulated and inhibit the early steps of CRC development.

2020-03-13 | GSE146786 | GEO

Chromosomal abnormalities in colorectal cancer

Project description:Microarray-based comparative genomic hybridization of CRC DNA samples from 17 patients who underwent colon resection for biopsy-proven invasive colorectal adenocarcinoma. Microarray-based comparative genomic hybridization of CRC DNA samples against a common reference.

2012-11-01 | E-GEOD-25228 | biostudies-arrayexpress

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