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S-adenosyl-methionine treatment selectively block liver cancer cell lines transformation and invasiveness by alterations of cancer- and invasion specific transcriptome and methylome (Bisulfite-Seq)

ABSTRACT: S-adenosyl methionine (SAM) is a ubiquitous methyl donor that was reported to have chemo- protective activity against liver cancer, however the molecular footprint of SAM has been unknown. We show here that SAM selectively inhibits growth, transformation and invasiveness of hepatocellular carcinoma cell lines but not normal primary liver cells. Analysis of the transcriptome of SAM treated and untreated cancer cell lines HepG2 and SKHep1 and primary liver cells reveals pathways involved in cancer and metastasis that are upregulated in cancer cells and silenced by SAM. Analysis of the methylome using bisulfite mapping of captured promoters and enhancers reveals that SAM hyper-methylates and silences genes in pathways of growth and metastasis that are activated in liver cancer cells. Depletion of two SAM silencing targets similarly reduces cellular transformation and invasiveness. Taken together these data provide a molecular foundation for SAM as an anticancer agent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87241 | GEO | 2016/09/23

SECONDARY ACCESSION(S): PRJNA343944

REPOSITORIES: GEO

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S-adenosyl-methionine treatment selectively block liver cancer cell lines transformation and invasiveness by alterations of cancer- and invasion specific transcriptome and methylome (RNA-Seq)

Project description:S-adenosyl methionine (SAM) is a ubiquitous methyl donor that was reported to have chemo- protective activity against liver cancer, however the molecular footprint of SAM has been unknown. We show here that SAM selectively inhibits growth, transformation and invasiveness of hepatocellular carcinoma cell lines but not normal primary liver cells. Analysis of the transcriptome of SAM treated and untreated cancer cell lines HepG2 and SKHep1 and primary liver cells reveals pathways involved in cancer and metastasis that are upregulated in cancer cells and silenced by SAM. Analysis of the methylome using bisulfite mapping of captured promoters and enhancers reveals that SAM hyper-methylates and silences genes in pathways of growth and metastasis that are activated in liver cancer cells. Depletion of two SAM silencing targets similarly reduces cellular transformation and invasiveness. Taken together these data provide a molecular foundation for SAM as an anticancer agent.

2016-09-23 | GSE87240 | GEO

Cancer growth and metastasis gene pathways are regulated by Methyl-CpG Binding Domain Protein 2 (Mbd2) in liver cancer and are altered by the ubiquitous methyl donor S-adenosyl methionine (SAM)

Project description:Perpose:We examined here whether SAM, which alters DNA methylation dynamics, interferes with the activity of Methyl-CpG Binding Domain Protein 2(Mbd2). Methods: mRNA of MBD2 knocked down of Skhep1 and HepG2 cells were generated by deep sequencing using Illumina GAIIx. DNA enriched by our designed microarray of MBD2 knocked down Skhep1 and HepG2 cells were also generated by deep sequencing using Illumina GAIIx. ChIP (Chromatin immunoprecipitation) was performed using ChIP-IT Express Kit with MBD2 antibody of SAM treated Skhep1, HepG2 and NorHep cells. concluds: SAM treatment results in reduction and redistribution of Mbd2 binding across genomic features in liver cancer cells, which is different from the response in untransformed liver cells. There is significant overlap between genes whose Mbd2 binding, DNA methylation and transcription are altered by Mbd2 depletion or SAM treatment. These data suggest that Mbd2 has a cancer specific footprint in binding, DNA methylation and transcription in liver cancer cells that is altered by SAM treatment. SAM selective impact on liver cancer cells is partially mediated by altering cancer specific Mbd2 binding. These data provide a molecular rationale for using either SAM or other Mbd2 modulators for treating/preventing liver cancer.

2021-02-10 | GSE166416 | GEO

A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness (methylation)

Project description:Cancer invasion and metastasis is the most morbid aspect of cancer and is governed by different cellular mechanisms than those driving the deregulated growth of tumors. We addressed here the question of whether a common DNA methylation signature of invasion exists in cancer cells from different origins that differentiates invasive from noninvasive cells. We identified a common DNA methylation signature consisting of hyper- and hypomethylation and determined the overlap of differences in DNA methylation with differences in mRNA expression using expression array analyses. A pathway analysis reveals that the hypomethylation signature includes some of the major pathways that were previously implicated in cancer migration and invasion such as TGF beta and ERBB2 triggered pathways. The relevance of these hypomethylation events in human tumors was validated by identification of the signature in several publicly available databases of human tumor transcriptomes. We shortlisted novel invasion promoting candidates and tested the role of four genes from the list C11orf68, G0S2, SHISA2 and TMEM156 in invasiveness using siRNA depletion. Importantly these genes are upregulated in human cancer specimens as determined by immunostaining of human normal and cancer breast, liver and prostate tissue arrays. Since these genes are activated in cancer they constitute a group of targets for specific pharmacological inhibitors of cancer invasiveness. Our study provides evidence that common DNA hypomethylation signature exists between cancer cells derived from different tissues, pointing to a common mechanism of cancer invasiveness in cancer cells from different origins.

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A common promoter hypomethylation signature in invasive breast, liver and prostate cancer cell lines reveals novel targets involved in cancer invasiveness (expression)

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S-adenosyl-methionine treatment selectively block liver cancer cell lines transformation and invasiveness by alterations of cancer- and invasion specific transcriptome and methylome

Project description:S-adenosyl-methionine treatment selectively block liver cancer cell lines transformation and invasiveness by alterations of cancer- and invasion specific transcriptome and methylome

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Proteomic analysis of the invasiveness of human bladder cancer cells

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Intestinal ablation of CKIalpha highlights invasiveness control

Project description:Wnt signaling, which drives the rapid self-renewal of the gut epithelium is causally associated with intestinal neoplasia. Here we show that CKIalpha is a activation depends on p53 and p21Waf1/Cip1: CKIÎ± ablation provokes activation of p53 and p21, which assume a pivotal role in suppressing invasive cancer. Dual loss of CKIalpha and either p53 or p21 results in rapid, rampant malignant signature denoted p53supinv (p53-suppressed invasiveness) that is conditionally induction of invasiveness. Like invasiveness control, the transcriptional suppression of p53supinv genes is largely mediated by p21, independently of cell cycle control, representing a novel tumor suppressor function of wild-type p53. 13 arrays of mice entrocytes herto or homozygot for gut specific KO of CKI alpha. Crossed with p53 or p21 KO mice.

2010-10-23 | E-GEOD-24760 | biostudies-arrayexpress

Intestinal ablation of CKIalpha highlights invasiveness control

Project description:Wnt signaling, which drives the rapid self-renewal of the gut epithelium is causally associated with intestinal neoplasia. Here we show that CKIalpha is a activation depends on p53 and p21Waf1/Cip1: CKIα ablation provokes activation of p53 and p21, which assume a pivotal role in suppressing invasive cancer. Dual loss of CKIalpha and either p53 or p21 results in rapid, rampant malignant signature denoted p53supinv (p53-suppressed invasiveness) that is conditionally induction of invasiveness. Like invasiveness control, the transcriptional suppression of p53supinv genes is largely mediated by p21, independently of cell cycle control, representing a novel tumor suppressor function of wild-type p53.

2010-10-23 | GSE24760 | GEO

Muscular invasiveness in bladder cancer

Project description:Patients with bladder cancer need frequent controls over long follow-up time due to high recurrence rate and risk of conversion to muscle invasive cancer with poor prognosis. We identified cancer-related molecular signatures in apparently healthy bladder in patients with subsequent muscular invasiveness during follow-up. Global proteomics of the normal tissue biopsies revealed specific proteome fingerprints in these patients prior to subsequent muscular invasiveness. In these presumed normal samples, we detected modulations of proteins previously associated with different cancer types. This study indicates that analyzing apparently healthy tissue of a cancer-invaded organ may predict disease progression.

2018-10-26 | PXD010260 | Pride

The landscape of promoter DNA hypomethylation in liver cancer (expression data)

Project description:Extensive loss of DNA methylation is a hallmark of cancer. The role of hypomethylation in altering gene expression in cancer cells has been poorly understood. Hepatic cellular carcinoma (HCC) is one of the most common human cancers. We use HCC as a model to investigate hypomethylation in cancer by a combination of methylated DNA immunoprecipitation and hybridization with comprehensive promoter arrays. We identify approximately 2,800 promoters that are hypomethylated in tumor samples. The hypomethylated promoters appear in clusters across the genome suggesting a high-level organization behind the epigenomic changes in cancer. The genes whose promoters are demethylated are mainly involved in cell growth, cell adhesion and communication, signal transduction, mobility and invasion; functions that are essential for cancer progression and metastasis. Previous studies suggested that MBD2 was involved in demethylation of uPA and MMP2 genes in human breast and prostate cancer cell lines. We extend these results here showing that whereas MBD2 depletion in normal liver cells has little or no effect, its depletion in the human hepatocellular carcinoma cell line HepG2 and the adenocarcinoma cell line SkHep1 results in suppression of cell growth, anchorage-independent growth and invasiveness, as well as an increase in promoter methylation and silencing of several of the genes that are hypomethylated in tumors. Our studies establish for the first time the rules governing hypomethylation of promoters in liver cancer and define the potential functional role of hypomethylation in cancer. Cancerous and normal adjacent tissue samples were obtained from 11 patients with HCC from the Chinese National Human Genome Center at Shanghai, China (Dr. Ze-Guang Han). For three patients, the cancer samples were dissected using the laser capture microdissection technique. Gene expression profiles for these patients were generated using Affymetrix expression microarrays.

2011-06-04 | E-GEOD-29721 | biostudies-arrayexpress

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