ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer

Gimeno-Valiente, Francisco; Riffo‐Campos, Ángela L.; Vallet-Sánchez, Azahara; Siscar-Lewin, Sofía; Gambardella, Valentina; Franco, Luís; Castillo, Josefa; López-Rodas, Gerardo

doi:10.1038/s41598-019-45411-9

Cited by 14 publications

(28 citation statements)

References 28 publications

(44 reference statements)

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“…Thus, we expect that nuCpos is applicable to prediction-based engineering and more effective for synthesizing functional elements. Similarly, nuCpos can also be used to examine whether DNA sequences of interest are suitable for nucleosome formation, as previously done with NuPoP [46, 47].…”

Section: Discussionmentioning

confidence: 99%

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Chemical map–based prediction of nucleosome positioning using the Bioconductor package nuCpos

Kato

Shimizu

Urano

2019

Preprint

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2 2 Background: 2 3 Methods for predicting nucleosome positioning include bioinformatics, 2 4 biophysical, and combined approaches. An advantage of bioinformatics 2 5 methods, which are based on in vivo nucleosome maps, is the use of natural 2 6 sequences that may contain previously unknown elements involved in 2 7 nucleosome positioning in vivo. The accuracy of such prediction attempts 2 8 reflects the genomic coordinate resolution of the nucleosome maps applied. 2 9 Thus, nucleosome maps constructed using Micrococcus nuclease (MNase), 3 0 which has a strong preference for A/T-rich sequences, may not be appropriate 3 1 for this purpose. In addition to MNase seq-based maps, base pair-resolution 3 2 chemical maps of in vivo nucleosomes from three different species (budding and 3 3 2 fission yeasts, and mouse) are currently available. However, these maps have 3 4 yet to be integrated into publicly available computational methods. 3 5 3 6Results:3 7We developed a Bioconductor package (named nuCpos) that uses chemical 3 8 maps to train duration hidden Markov models (dHMMs) to predict nucleosome 3 9positioning. The accuracy of chemical map-based prediction was higher than 4 0 that of the previously developed MNase seq-based approach. With our method, 4 1 predicted nucleosome occupancy reasonably matched in vivo observations and 4 2 was not affected by A/T nucleotide frequency. Effects of genetic alterations on 4 3 nucleosome positioning that had been observed in living yeast could also be 4 4 predicted. In addition to dHMM-based prediction, nuCpos can calculate 4 5 individual histone binding affinity (HBA) scores for given 147-bp sequences to 4 6 examine their suitability for nucleosome formation. Local HBA scores for 13 4 7 overlapping nucleosomal DNA subsegments can also be calculated. HBA and 4 8 local HBA scores for various sequences agreed well with previous in vitro and in 4 9vivo studies. Furthermore, our results suggest that nucleosomal subsegments 5 0 that are disfavored in different rotational settings contribute to the defined 5 1 positioning of nucleosomes. 5 2 5 3 Conclusions: 5 4Our results demonstrate that chemical map-based statistical models are 5 5 beneficial for studying nucleosomal DNA features. Studies employing nuCpos 5 6software can enhance understanding of chromatin regulation and the 5 7

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Section: Discussionmentioning

confidence: 99%

“…These nucleosomes are suitable for in silico reproduction of in vivo observations. Importantly, for the currently available bioinformatics method NuPoP, the reliability of locus-level nucleosome prediction has seldom been demonstrated, despite its wide use in previous studies [38–47].…”

Section: Introductionmentioning

confidence: 99%

Chemical map–based prediction of nucleosome positioning using the Bioconductor package nuCpos

Kato

Shimizu

Urano

2019

Preprint

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“…Western blot analyses. Western blot analyses were carried out essentially as previously described 40 . Briefly, cultured cells were extracted with RIPA buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1% Triton X-100, 0.1% SDS, 0.5% deoxycholic acid sodium salt (w/v)) supplemented with 2 μl/ml protease inhibitor cocktail (Sigma).…”

Section: Methodsmentioning

confidence: 99%

EPDR1 up-regulation in human colorectal cancer is related to staging and favours cell proliferation and invasiveness

Gimeno-Valiente

Riffo‐Campos

Ayala

et al. 2020

Sci Rep

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The finding of novel molecular markers for prediction or prognosis of invasiveness in colorectal cancer (cRc) constitutes an appealing challenge. Here we show the up-regulation of EPDR1 in a prospective cohort of 101 CRC patients, in a cDNA array of 43 patients and in in silico analyses. EPDR1 encodes a protein related to ependymins, a family of glycoproteins involved in intercellular contacts. A thorough statistical model allowed us to conclude that the gene is significantly up-regulated in tumour tissues when compared with normal mucosa. these results agree with those obtained by the analysis of three publicly available databases. EPDR1 up-regulation correlates with the tnM staging parameters, especially t and M. Studies with cRc cell lines revealed that the methylation of a cpG island controls EPDR1 expression. siRNA knocking-down and overexpression of the gene following transient plasmid transfection, showed that EPDR1 favours cell proliferation, migration, invasiveness and adhesion to type I collagen fibres, suggesting a role in epithelial to mesenchymal transition. Both statistical and functional analysis correlated EPDR1 overexpression with invasiveness and dissemination of tumour cells, supporting the inclusion of EPDR1 in panels of genes used to improve molecular subtyping of cRc. eventually, EPDR1 may be an actionable target. Colorectal cancer (CRC) is one of the most common malignancies worldwide 1. In spite of the progresses of precision medicine, the long-term survival of patients with advanced metastatic disease is still poor 2 and the burden of CRC is expected to increase by 60% in the next decade 1. Nevertheless, this disease is a good candidate for screening programmes 3 and its early detection improve treatment and survival. Most of CRC-related death is due to tumour metastasis 4 and, therefore, finding of molecular markers for prediction or prognosis of invasiveness, which could be added to the available repertoire of potential markers 5-7 , constitutes an appealing challenge. This is particularly attractive in view of the growing interest in improving the clinical stratification of CRC 8,9. This reason, together with the risks of metastatic dissemination, makes especially interesting the identification of potential actionable targets in CRC. The EPDR1 gene codes for a protein related to ependymins, a family of piscine brain glycoproteins 10. Ependymins, encoded by Epd genes, are transmembrane proteins that play a role in intercellular contacts between neural cells 11. It was early suggested that their extracellular domain may display antiadhesive properties 12 and it shows a calcium-dependent ability to interact with collagen fibrils 13 .

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“…As the dysregulation of this enzyme has been associated with CRC [ 8 ], we further developed the initial work with CRC cell lines [ 1 ] and showed that ZNF518B is up-regulated in patients of colorectal cancer. By silencing the gene in CRC cell lines, it was demonstrated that its expression favours cell migration, invasiveness and other phenotypic variations, which suggests that the gene may be involved in the epithelial-to-mesenchymal transition (EMT) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

Gimeno-Valiente

Riffo‐Campos

Torres

et al. 2021

Cancers

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The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.

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ZNF518B gene up-regulation promotes dissemination of tumour cells and is governed by epigenetic mechanisms in colorectal cancer

Cited by 14 publications

References 28 publications

Chemical map–based prediction of nucleosome positioning using the Bioconductor package nuCpos

Chemical map–based prediction of nucleosome positioning using the Bioconductor package nuCpos

EPDR1 up-regulation in human colorectal cancer is related to staging and favours cell proliferation and invasiveness

Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer

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