γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

Kim, Sung Eun; Hinoue, Toshinori; Kim, Michael S.; Sohn, Kyoung Jin; Cho, Robert C.; Cole, Peter D.; Weisenberger, Daniel J.; Laird, Peter W.; Kim, Young In

doi:10.1007/s12263-014-0444-0

Cited by 12 publications

(11 citation statements)

References 66 publications

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“…GGH is involved in the turnover of cellular folates, since a reduction in the GGH expression increases the cellular folate content and poly-gamma glutamate. In lung adenocarcinoma, the GGH expression was lower and correlated with higher folate concentrations and increased DNA methylation [ 57 ]. In the context of KCNK3 dysfunction and PAH, a downregulation of GGH may have significant implications for the pulmonary vascular cell phenotype.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Ribeuz

Dumont

Ruellou

et al. 2020

IJMS

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The physiopathology of pulmonary arterial hypertension (PAH) is characterized by pulmonary artery smooth muscle cell (PASMC) and endothelial cell (PAEC) dysfunction, contributing to pulmonary arterial obstruction and PAH progression. KCNK3 loss of function mutations are responsible for the first channelopathy identified in PAH. Loss of KCNK3 function/expression is a hallmark of PAH. However, the molecular mechanisms involved in KCNK3 dysfunction are mostly unknown. To identify the pathological molecular mechanisms downstream of KCNK3 in human PASMCs (hPASMCs) and human PAECs (hPAECs), we used a Liquid Chromatography-Tandem Mass Spectrometry-based proteomic approach to identify the molecular pathways regulated by KCNK3. KCNK3 loss of expression was induced in control hPASMCs or hPAECs by specific siRNA targeting KCNK3. We found that the loss of KCNK3 expression in hPAECs and hPASMCs leads to 326 and 222 proteins differentially expressed, respectively. Among them, 53 proteins were common to hPAECs and hPASMCs. The specific proteome remodeling in hPAECs in absence of KCNK3 was mostly related to the activation of glycolysis, the superpathway of methionine degradation, and the mTOR signaling pathways, and to a reduction in EIF2 signaling pathways. In hPASMCs, we found an activation of the PI3K/AKT signaling pathways and a reduction in EIF2 signaling and the Purine Nucleotides De Novo Biosynthesis II and IL-8 signaling pathways. Common to hPAECs and hPASMCs, we found that the loss of KCNK3 expression leads to the activation of the NRF2-mediated oxidative stress response and a reduction in the interferon pathway. In the hPAECs and hPASMCs, we found an increased expression of HO-1 (heme oxygenase-1) and a decreased IFIT3 (interferon-induced proteins with tetratricopeptide repeats 3) (confirmed by Western blotting), allowing us to identify these axes to understand the consequences of KCNK3 dysfunction. Our experiments, based on the loss of KCNK3 expression by a specific siRNA strategy in control hPAECs and hPASMCs, allow us to identify differences in the activation of several signaling pathways, indicating the key role played by KCNK3 dysfunction in the development of PAH. Altogether, these results allow us to better understand the consequences of KCNK3 dysfunction and suggest that KCNK3 loss of expression acts in favor of the proliferation and migration of hPASMCs and promotes the metabolic shift and apoptosis resistance of hPAECs.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Ribeuz

Dumont

Ruellou

et al. 2020

IJMS

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“…In both human colon and breast cancer cell lines, the overexpression of GGH was found to be connected with global DNA methylation and the activity of DNA methyltransferase, which might influence the gene expression in critical biological pathways. Thus, it consequently had an impact on the regulation of cell cycle, cellular growth, and proliferation . Methylation of CpG1 islands in the GGH promoter region could remarkably reduce the GGH mRNA expression and improve treatment outcomes in pediatric patients with acute leukemia .…”

Section: Discussionmentioning

confidence: 99%

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis

Qiu

et al. 2018

J of Cellular Biochemistry

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As a unique subtype of esophageal cancer, synchronous multiple primary esophageal squamous cell carcinomas (ESCCs) mostly occur in Asian patients with alcohol and/or tobacco abuse, or with a family history of cancer. Multiple ESCCs are associated with poor clinical outcomes. Growing evidence has addressed that long noncoding RNAs (lncRNAs) are involved in the carcinogenesis of various malignancies. We compared the lncRNA and messenger RNA (mRNA) profiles between solitary and multiple ESCC tissues through microarray analysis, aiming at studying their different mechanisms in tumor development. As a result, in multiple ESCCs, a total of 5257 lncRNAs and 3371 mRNAs were consistently differentially expressed compared with solitary ESCC, including 2986 upregulated and 2271 downregulated lncRNAs, and 2313 upregulated, and 1058 downregulated mRNAs. We validated the results in four differentially expressed lncRNAs using quantitative real‐time polymerase chain reaction. There were 38 and 20 pathways significantly related to up‐ and downregulated transcripts. The pathways associated with mostly enriched up‐ and downregulated mRNAs were hsa01200 (carbon metabolism) and hsa05221 (acute myeloid leukemia‐ homo sapiens [human]). Gene ontology analysis suggested that upregulated and downregulated mRNAs were mainly enriched in bounding membrane of organelle involved in the cellular component and positive regulation of transport involved in the biological process. Further analysis identified 189 differentially expressed paired antisense lncRNAs and relative sense mRNA, as well as 2134 differentially expressed long intergenic noncoding RNAs and their adjacent mRNA pairs. In conclusion, the aberrantly expressed lncRNAs might play a role in the carcinogenesis of multiple ESCCs and could be candidates as diagnostic biomarkers and therapeutic targets.

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“…Under conditions of folate deficiency, uracil is synthesized and incorporated in the DNA instead of thymidine [ 27 ], a process that has been associated with the generation of point mutations, single- and double-strand DNA breaks, and chromosome breakage [ 28 , 29 ]. In addition, folate deficiency has been linked to impaired mitochondrial metabolism with accumulation of DNA-damaging reactive oxygen species [ 30 , 31 , 32 ], and recent work further suggests that GGH-dependent reduction of the intracellular folic acid concentration may also induce epigenetic alterations [ 9 , 33 ], which can impact genetic integrity [ 34 , 35 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer

Melling

Rashed

Schroeder

et al. 2017

IJMS

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γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.

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γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

Cited by 12 publications

References 66 publications

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Proteomic Analysis of KCNK3 Loss of Expression Identified Dysregulated Pathways in Pulmonary Vascular Cells

Differential expression profiles of long noncoding RNAs in synchronous multiple and solitary primary esophageal squamous cell carcinomas: A microarray analysis

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer

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