Exploring targets of TET2-mediated methylation reprogramming as potential discriminators of prostate cancer progression
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ABSTRACT:
PROVIDER: PRJNA527318 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8735110_1.fastq.gz | Fastqsanger.gz | |||
| SRR8735110_2.fastq.gz | Fastqsanger.gz | |||
| SRR8735120.fastq.gz | Fastqsanger.gz | |||
| SRR8735120_1.fastq.gz | Fastqsanger.gz | |||
| SRR8735120_2.fastq.gz | Fastqsanger.gz |
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Project description:Background: Global DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology. Results: Using a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes – ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX – exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n=423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n=50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n=19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site. Conclusions: Our study identifies seven genes governed by TET2 loss in PCa which exhibit association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.
2019-04-05 | GSE128399 | GEO
Project description:BackgroundGlobal DNA methylation alterations are hallmarks of cancer. The tumor-suppressive TET enzymes, which are involved in DNA demethylation, are decreased in prostate cancer (PCa); in particular, TET2 is specifically targeted by androgen-dependent mechanisms of repression in PCa and may play a central role in carcinogenesis. Thus, the identification of key genes targeted by TET2 dysregulation may provide further insight into cancer biology.ResultsUsing a CRISPR/Cas9-derived TET2-knockout prostate cell line, and through whole-transcriptome and whole-methylome sequencing, we identified seven candidate genes-ASB2, ETNK2, MEIS2, NRG1, NTN1, NUDT10, and SRPX-exhibiting reduced expression and increased promoter methylation, a pattern characteristic of tumor suppressors. Decreased expression of these genes significantly discriminates between recurrent and non-recurrent prostate tumors from the Cancer Genome Atlas (TCGA) cohort (n = 423), and ASB2, NUDT10, and SRPX were significantly correlated with lower recurrence-free survival in patients by Kaplan-Meier analysis. ASB2, MEIS2, and SRPX also showed significantly lower expression in high-risk Gleason score 8 tumors as compared to low or intermediate risk tumors, suggesting that these genes may be particularly useful as indicators of PCa progression. Furthermore, methylation array probes in the TCGA dataset, which were proximal to the highly conserved, differentially methylated sites identified in our TET2-knockout cells, were able to significantly distinguish between matched prostate tumor and normal prostate tissues (n = 50 pairs). Except ASB2, all genes exhibited significantly increased methylation at these probes, and methylation status of at least one probe for each of these genes showed association with measures of PCa progression such as recurrence, stage, or Gleason score. Since ASB2 did not have any probes within the TET2-knockout differentially methylated region, we validated ASB2 methylation in an independent series of matched tumor-normal samples (n = 19) by methylation-specific qPCR, which revealed concordant and significant increases in promoter methylation within the TET2-knockout site.ConclusionsOur study identifies seven genes governed by TET2 loss in PCa which exhibit an association between their methylation and expression status and measures of PCa progression. As differential methylation profiles and TET2 expression are associated with advanced PCa, further investigation of these specialized TET2 targets may provide important insights into patterns of carcinogenic gene dysregulation.
| S-EPMC6438015 | biostudies-literature
Project description:Prostate cancer is the most common cancer in men. We identified that miR-29 family is the most androgen-responsive miRNA in hormone-refractory prostate cancer cells. For the screening of miR-29b target, we performed microarray analysis in two prostate cancer cells. Because TET2 is the primary target of miR-29 family by our analysis, we also performed TET2 signaling by microarray. In order to investigate the downsteam signals mediated by TET2 and miR-29b, we performed comprehensive analysis of gene expression in positive prostate cancer cell lines after siTET2 or miR-29b treatment. Observation of gene expression changes after treatmet with siRNA targeting TET2 or miR-29b in prostate cancer cell lines with microarray.
2015-09-01 | E-GEOD-66038 | biostudies-arrayexpress
Project description:Tet2 regulates gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. Profiling the genomic locations of 5-hydroxymethylcytosine after Tet2 manipulation can inform us of the targets of Tet2 regulation. We profiled hydroxymethylcytosine in Tet2 knockout neurons to determine the targets of Tet2 in neurons.
2023-03-25 | GSE199597 | GEO
Project description:Tet2 regulates gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. Profiling the genomic locations of 5-hydroxymethylcytosine after Tet2 manipulation can inform us of the targets of Tet2 regulation. We profiled hydroxymethylcytosine in Tet2 ovexpressing neurons to determine the targets of Tet2 in neurons.
2023-03-17 | GSE198910 | GEO
Project description:Ten-eleven translocation-2 (TET2) is a member of the methylcytosine dioxygenase family of enzymes implicated in cancer and in aging due to its role as a global epigenetic modifier. TET2 has a large N-terminal domain followed by a catalytic C-terminal. Previous reports have demonstrated that the catalytic domain remains active independent of the N-terminal domain. As such, the function of the N-terminus of this large protein remains poorly characterized. Here, we identify that several isoforms of the 14-3-3 family of proteins bind TET2. 14-3-3s bind TET2 when phosphorylated at serine 99 (S99). AMPK-mediated phosphorylation at S99 promotes TET2 stability and increases global DNA 5-hydroxymethylcytosine. 14-3-3s’ interaction with TET2 serves to protect S99 phosphorylation. Disruption of this interaction leads to both reduced TET2 phosphorylation and decreased protein stability. Furthermore, we identify that the protein phosphatase 2A (PP2A) can interact with TET2 and dephosphorylates S99. Collectively, our study provides novel insights into the role of the N-terminal domain in TET2 regulation. Moreover, they demonstrate the dynamic nature of TET2 protein regulation that could have therapeutic implications for disease states resulting from reduced TET2 levels and/or activity.
2020-01-13 | PXD016160 | Pride
Project description:Exploring the underlying mechanism by which circHNRNPU_603aa exerted carcinogenesis and its potential targets in MM
| PRJNA730289 | ENA
Project description:Prostate cancer is the most common cancer in men. We identified that miR-29 family is the most androgen-responsive miRNA in hormone-refractory prostate cancer cells. For the screening of miR-29b target, we performed microarray analysis in two prostate cancer cells. Because TET2 is the primary target of miR-29 family by our analysis, we also performed TET2 signaling by microarray. In order to investigate the downsteam signals mediated by TET2 and miR-29b, we performed comprehensive analysis of gene expression in positive prostate cancer cell lines after siTET2 or miR-29b treatment.
2015-09-01 | GSE66038 | GEO
Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
2020-09-09 | PXD020550 | Pride
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation Gene expression profiles from WT and Tet2-/- sorted LSK and myeloid progenitors (CMP and GMP) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.
2011-07-01 | E-GEOD-27816 | biostudies-arrayexpress