Is DNA methylation the new guardian of the genome?

Hoffman, Robert M.

doi:10.1186/s13039-017-0314-8

Cited by 32 publications

(19 citation statements)

References 53 publications

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“…The excessive and aberrant use of MET in cancer is readily observed in [ 11 C]MET PET imaging, where high uptake of [ 11 C]MET results in a very strong and selective tumor signal compared with normal tissue background. [ 11 C]MET is superior to [ 18 C] fluorodeoxyglucose (FDG) for PET imaging, suggesting MET dependence is more tumor-specific than glucose dependence [19,20].…”

Section: Resultsmentioning

confidence: 99%

Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention

Kawaguchi

Han

et al. 2018

Cell Cycle

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The elevated methionine (MET) use by cancer cells is termed MET dependence and may be the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo. We previously reported that rMETase, administrated by intra-peritoneal injection (ip-rMETase), could inhibit tumor growth in a patient-derived orthotopic xenograft (PDOX) model of a BRAF-V600E mutant melanoma. In the present study, we compared ip-rMETase and oral rMETase (o-rMETase) for efficacy on the melanoma PDOX. Melanoma PDOX nude mice were randomized into four groups of 5 mice each: untreated control; ip-rMETase (100 units, i.p., 14 consecutive days); o-rMETase (100 units, p.o., 14 consecutive days); o-rMETase+ip-rMETase (100 units, p.o.+100 units, i.p., 14 consecutive days). All treatments inhibited tumor growth on day 14 after treatment initiation, compared to untreated control (ip-rMETase, p<0.0001; o-rMETase, p<0.0001; o-rMETase+ip-rMETase, p<0.0001). o-rMETase was significantly more effective than ip-rMETase (p = 0.0086). o-rMETase+ip-rMETase was significantly more effective than either mono-therapy: ip-rMETase, p = 0.0005; or o-rMETase, p = 0.0367. The present study is the first demonstrating that o-rMETase is effective as an anticancer agent. The results of the present study indicate the potential of clinical development of o-rMETase as an agent for chronic cancer therapy and for cancer prevention and possibly for life extension since dietary MET reduction extends life span in many animal models.

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Section: Resultsmentioning

confidence: 99%

Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention

Kawaguchi

Han

et al. 2018

Cell Cycle

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“…Recent evidence underlines that DNA methylation is another “guardian of the genome” [ 41 ]. It is generally accepted that DNA hypomethylation destabilizes the genome [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Melnik

2017

Nutr Metab (Lond)

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There is accumulating evidence that milk shapes the postnatal metabolic environment of the newborn infant. Based on translational research, this perspective article provides a novel mechanistic link between milk intake and milk miRNA-regulated gene expression of the transcription factor p53 and DNA methyltransferase 1 (DNMT1), two guardians of the human genome, that control transcriptional activity, cell survival, and apoptosis. Major miRNAs of milk, especially miRNA-125b, directly target TP53 and complex p53-dependent gene regulatory networks. TP53 regulates the expression of key genes involved in cell homeostasis such as FOXO1, PTEN, SESN1, SESN2, AR, IGF1R, BAK1, BIRC5, and TNFSF10. Nuclear interaction of p53 with DNMT1 controls gene silencing. The most abundant miRNA of milk and milk fat, miRNA-148a, directly targets DNMT1. Reduced DNMT1 expression further attenuates the activity of histone deacetylase 1 (HDAC1) involved in the regulation of chromatin structure and access to transcription. The presented milk-mediated miRNA-p53-DNMT1 pathway exemplified at the promoter regulation of survivin (BIRC5) provides a novel explanation for the epidemiological association between milk consumption and acne vulgaris and prostate cancer. Notably, p53- and DNMT1-targeting miRNAs of bovine and human milk survive pasteurization and share identical seed sequences, which theoretically allows the interaction of bovine miRNAs with the human genome. Persistent intake of milk-derived miRNAs that attenuate p53- and DNMT1 signaling of the human milk consumer may thus present an overlooked risk factor promoting acne vulgaris, prostate cancer, and other p53/DNMT1-related Western diseases. Therefore, bioactive miRNAs of commercial milk should be eliminated from the human food chain.

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“…As previously reported, CTC clusters, which contain fibroblasts, may enhance metastasis and the fibroblasts may confer vascular specificity (2-7). Because choline is a precursor of methionine, lower methionine levels in CDD mice may inhibit methionine metabolism which is necessary for metastasis, and may also disturb migration of fibroblasts (14)(15)(16)(17)(18)(19).…”

Section: Resultsmentioning

confidence: 99%

“…The median of red fluorescent protein (RFP)-expressing cells (CTCs) in 10 μl blood from heart or portal circulation and total green fluorescent protein (GFP)expressing fibroblast-like cells remaining on the dishes after a 7-day blood culture of EL4 lymphoma-bearing CD and CDD mice are shown. methionine metabolism, which may have been the result of deficiency in choline (14)(15)(16)(17)(18)(19).…”

Section: Resultsmentioning

confidence: 99%

Choline-deficient-diet Decreases Fibroblasts in the Circulating Tumor Cell (CTC) Microenvironment

et al. 2019

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Background/Aim: Circulating tumor cells (CTCs) may have an important role in metastasis. CTC clusters, which contain fibroblasts, indicate poor prognosis. In the present study, we used our malignant lymphoma metastatic mouse model to compare the effect of a choline-deficient-diet (CDD) and the control diet (CD) on fibroblasts in CTCs. Materials and Methods: We compared the number and morphology of CTCs in CDD and CD mice using color-coded imaging with fluorescent proteins. Malignant lymphoma EL4 cells expressing RFP were injected in the spleen of transgenic C57B/6-GFP mice, which were fed a CDD or CD. Two weeks later, we harvested and observed the number of CTCs and fibroblast-like cells both in heart blood and portal blood. Imaging of CTC morphology was performed with smeared glass slides and in culture. Results and Conclusion: There was no significant difference in the number of CTCs between CDD and CD mice. The number of fibroblast-like cells in the CTC microenvironment in CD mouse portal blood was significantly larger than in CDD mouse portal blood. These differences may be caused by deficiency in choline that leads to less metastasis in choline-deficient-diet-induced fatty liver. Circulating tumor cells (CTCs) were discovered in the 19th century (1). CTCs have an important role in metastasis and indicate poor cancer prognosis (2). Large numbers of CTCs indicate extremely poor prognosis. CTC clusters which comprise multiple cell types such as fibroblasts may have higher metastatic potential (3-7). We have investigated the mechanism of liver metastasis in fatty liver, and showed that fewer metastases and cancer-associated fibroblasts (CAFs) occurred in choline-deficient-diet-induced fatty liver (8). We have previously developed a syngeneic mouse model of malignant lymphoma using murine EL-4 lymphoma cells expressing red fluorescent protein (RFP) implanted in transgenic mice expressing green fluorescent protein (GFP), and described the color-coded imaging of the CTC microenvironment (8-12). In the present study, using the EL4 mouse model of metastatic lymphoma, the fibroblasts present in the CTC microenvironment were compared between mice fed a choline-deficient-diet (CDD) and control diet (CD), and analysed by color-coded imaging. Materials and Methods Cell line and culture conditions. EL4, mouse malignant lymphoma cells, were engineered to stably express red fluorescent protein (RFP) as previously reported (9-11). The cells were maintained in RPMI 1640 medium (Gibco-BRL, Grand island, NY, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin and streptomycin (Gibco-BRL). The cells were cultured in a humidified atmosphere containing 5% CO 2 at 37˚C.

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Is DNA methylation the new guardian of the genome?

Cited by 32 publications

References 53 publications

Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention

Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention

Milk disrupts p53 and DNMT1, the guardians of the genome: implications for acne vulgaris and prostate cancer

Choline-deficient-diet Decreases Fibroblasts in the Circulating Tumor Cell (CTC) Microenvironment

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