Nickel(II) Inhibits Tet-Mediated 5-Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II)

Yin, Ruichuan; Mo, Jiezhen; Dai, Jiayin; Wang, Hailin

doi:10.1021/acschembio.7b00261

Cited by 40 publications

(21 citation statements)

References 21 publications

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“…We found that knocking out TET2 in 786-O ccRCC cells can compromise the induction of 5hmC upon vitamin C treatment (Fig 2G). Next, we used a pan-TET inhibitor, NiCl 2 [12], to inhibit TET enzymes. However, TET2 knockout in 786-O cells did not completely block the establishment of intracellular 5hmC by vitamin C treatment, suggesting that vitamin C can also restore 5hmC catalyzed by other TET enzymes.…”

Section: Resultsmentioning

confidence: 99%

“…However, TET2 knockout in 786-O cells did not completely block the establishment of intracellular 5hmC by vitamin C treatment, suggesting that vitamin C can also restore 5hmC catalyzed by other TET enzymes. Next, we used a pan-TET inhibitor, NiCl 2 [12], to inhibit TET enzymes. NiCl 2 treatment blocked vitamin C-induced 5hmC restoration in both 786-O and A498 cells ( Fig 2I).…”

Section: Resultsmentioning

confidence: 99%

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Restoration of 5‐hydroxymethylcytosine by ascorbate blocks kidney tumour growth

Ding

et al. 2018

EMBO Reports

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Loss of 5-hydroxymethylcytosine (5hmC) occurs frequently in a wide variety of tumours, including clear-cell renal cell carcinoma (ccRCC). It remains unknown, however, whether the restoration of 5hmC patterns in tumours could have therapeutic efficacy. Here, we used sodium L-ascorbate (vitamin C, AsANa) and the oxidation-resistant form L-ascorbic acid 2-phosphate sesquimagnesium (APM) for the restoration of 5hmC patterns in ccRCC cells. At physiological concentrations, both show anti-tumour efficacy during long-term treatment Strikingly, global 5hmC patterns in ccRCC cells after treatment resemble those of normal kidney tissue, which is observed also in treated xenograft tumours, and in primary cells from a ccRCC patient. Further, RNA-seq data show that long-term treatment with vitamin C changes the transcriptome of ccRCC cells. Finally, APM treatment induces less non-specific cell damage and shows increased stability in mouse plasma compared to AsANa. Taken together, our study provides proof of concept for an epigenetic differentiation therapy of ccRCC with vitamin C, especially APM, at low doses by 5hmC reprogramming.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Restoration of 5‐hydroxymethylcytosine by ascorbate blocks kidney tumour growth

Ding

et al. 2018

EMBO Reports

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“…Similarly, Ni has been shown to cause hypermethylation in TSGs like P53 of Chinese hamster cell line by facilitating the increased binding and activity of DNMT1 [96]. Alternatively, Yin et al showed that Ni can inhibit the activity of TET enzymes by displacing Fe(II), a possible mode of hypermethylating TSG [97].…”

Section: Heavy Metals Deregulate 5-hydroxymethylcytosinementioning

confidence: 99%

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

et al. 2017

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Epigenetic modes of gene regulation are important for physiological conditions and its aberrant changes can lead to disease like cancer. 5-hydroxymethylcytosine (5hmC) is an oxidized form of 5-methylcytosine (5mC) catalyzed by Ten Eleven Translocation (TET) enzymes. 5hmC is considered to be a demethylation intermediate and is emerging as a stable and functional base modification. The global loss of 5hmC level is commonly observed in cancers and tumorigenic germline mutations in IDH, SDH and FH are found to be inhibiting TET activity. Although a global loss of 5hmC is characteristic in cancers, locus-specific 5hmC gain implicates selective gene expression control. The definitive role of 5hmC as a tumor suppressing or promoting modification can be deduced by identifying locus-specific 5hmC modification in different types of cancer. Determining the genes carrying 5hmC modifications and its selective variation will open up new therapeutic targets. This review outlines the role of global and locus-specific changes of 5hmC in cancers and the possible mechanisms underlying such changes. We have described major cellular factors that influence 5hmC levels and highlighted the significance of 5hmC in tumor micro environmental condition like hypoxia.

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“…14 On the other hand, we found that nickel(II) inhibited Tet-mediated oxidation of 5mC to 5hmC by affinity displacement of the cofactor Fe(II) from the catalytic center of Tet dioxygenases. 15,16 Liu et al showed that arsenite, a ubiquitous environmental pollutant but also a therapeutic drug, could inhibit the catalytic activity of Tet proteins in vitro and ex vivo because of its high binding affinity toward the zinc fingers of Tet proteins. 17 The compounds with a structure similar to 2-oxoglutarate, for example, an oncometabolite 2-hydroxyglutarate and a synthetic dimethyloxalylglycine 2-oxoglutarate, can act as competitive inhibitors to reduce TET-mediated 5mC oxidation.…”

Section: ■ Introductionmentioning

confidence: 99%

Idarubicin Stimulates Cell Cycle- and TET2-Dependent Oxidation of DNA 5-Methylcytosine in Cancer Cells

Zhong

Han

et al. 2019

Chem. Res. Toxicol.

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The topoisomerase II inhibitor idarubicin (Ida) is an effective anticancer anthracycline drug and has been used for clinical therapies of multiple cancers. It is wellknown that Ida and its analogues can induce DNA double strand breakage (DSB) by inhibiting topoisomer II and kill tumor cells. To date, it remains unknown whether they alter DNA epigenomes. Here, we show that Ida significantly stimulates the oxidation of a key epigenetic mark DNA 5methyl-2′-deoxycytidine (5mC), which results in elevation of 5-hydroxymethyl-2′-deoxycytidine (5hmC) in four tested cell lines. Similarly, Ida analogues also display elevated 5hmC. DSB-causing topoisomer II inhibitor etopside fails to induce 5hmC change even at very high dose, which suggests the independence of the DSB. Moreover, the structure comparison supports that the histone eviction-associated amino sugar moiety is a characteristic of the anthracyclines required to promote the 5hmC elevation. Noteworthy, we also found that the 5mC oxidation is also cell-cycle dependent and mainly occurs during the S and G2/M phases. TET2 depletion diminishes the observed 5hmC elevation, which suggests that the Ida stimulation of 5hmC formation is mainly TET2-dependent. Deepsequencing shows that 5hmC increases in all regions of the tested genome of T47D cells. The observation of a novel effect of Ida as well as other anthracycline compounds on epigenetic DNA modifications may help to further elucidate their biological and clinical effects.

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Nickel(II) Inhibits Tet-Mediated 5-Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II)

Cited by 40 publications

References 21 publications

Restoration of 5‐hydroxymethylcytosine by ascorbate blocks kidney tumour growth

Restoration of 5‐hydroxymethylcytosine by ascorbate blocks kidney tumour growth

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

Idarubicin Stimulates Cell Cycle- and TET2-Dependent Oxidation of DNA 5-Methylcytosine in Cancer Cells

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