3-Deazaneplanocin: A new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60

Glazer, Robert I.; Hartman, Kathleen D.; Knode, Marian C.; Richard, M.M.; Chiang, Peter K.; Tseng, Christopher K. H.; Márquez, Víctor E.

doi:10.1016/0006-291x(86)90048-3

Cited by 145 publications

(97 citation statements)

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“…DZNep is a carbocyclic analog of adenosine synthesized more than 20 years ago as an inhibitor of S-adenosylhomocysteine hydrolase, which has therapeutic potential as an anticancer or antiviral drug. 21 DZNep has recently aroused interest for its unique features; it decreases the expressions of EZH2, SUZ12, and EED with inhibition of H3K27 methylation and induces apoptosis in cancer cells but not in normal cells. 22,23 ATL cell lines were sensitive to DZNep and their cell proliferation was attenuated at onetenth of the concentration used in these studies.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, ATL samples were strongly positive for H3K27me3, and were sensitive to 3-deazaneplanocin A (DZNep), a histone methylation inhibitor. [21][22][23] It has recently been shown that HDAC inhibitor panobinostat (PS, also known as LBH589) depletes the levels of EZH2, SUZ12, and EED and induces apoptotic death in leukemia cells. 24 Deregulation of PcG protein genes with overexpressed EZH2 in ATL cells suggests that ATL is one of the appropriate target diseases for such epigenetic therapy.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

Sasaki¹,

Imaizumi²,

Hasegawa³

et al. 2011

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundEnhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression. Design and MethodsIn this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance. ResultsSignificantly higher levels of Enhancr of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4 + T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells ConclusionsThese findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.Key words: adult T-cell leukemia/lymphoma, human T-cell leukemia virus type-1, Enhancer of zeste homolog 2, H3K27me3. 2011;96(4):712-719. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, Mano H, Marquez VE, Hayashi T, Yanagihara K, Moriwaki Y, Miyazaki Y, Kamihira S, and Yamada Y. Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy HaematologicaOverexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

Sasaki¹,

Imaizumi²,

Hasegawa³

et al. 2011

Haematologica

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“…In contrast to DNA demethylating agents and HDAC inhibitors, no therapies that directly target histone methylation are clinically available, despite the fact that there is experimental evidence for a potential therapeutic benefit for this approach. Most experimental work on the inhibition of EZH2 activity has used the carbocyclic adenosine analog 3-deazaneplanocin (DZNep), a derivative of the naturally occurring antibiotic neplanocin-A, in which ribose is replaced by a cyclopentyl ring (49). DZNep inhibits S-adenosylhomocysteine hydrolase, a component of the methionine cycle, resulting in accumulation of the inhibitory S-adenosylhomocysteine with a knock-on disruption of methylation of substrates by EZH2 (Fig.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Aberrations of EZH2 in Cancer

Chase

Cross

2011

Clinical Cancer Research

488

428

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Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future. Clin Cancer Res; 17(9); 2613-8. Ó2011 AACR.

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“…With the aim of finding new prevention combinations, we studied the effect of cotreatment with 3-deazaneplanocin (DZNep) and EGCG on the skin cancer cells. DZNep, a deazaadenosine analog, is an inhibitor of the enzyme S-adenosyl homocysteine (AdoHcy) hydrolase (109)(110)(111). Inhibition of this enzyme results in accumulation of AdoHcy which limits the methyl groups available for use by S-adenosyl-L-methionine-dependent methyl transferases (111).…”

Section: Epigenetic Impact Of Dietary Agents (Sulforaphane and Green mentioning

confidence: 99%

Epigenetic Cancer Prevention Mechanisms in Skin Cancer

Saha

Hornyak

Eckert

2013

AAPS J

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Abstract. Epigenetics is an important emerging area for study of mechanisms of cancer prevention. In recent years, it has been realized that cancer prevention agents, derived from natural dietary sources, impact cancer cell survival by modulating epigenetic processes. In the present manuscript, we review key epigenetic regulatory mechanisms and examine the impact of sulforaphane and green tea polyphenols on these processes. We also discuss available information on the epigenetics in the context of skin cancer. These studies indicate that diet-derived chemopreventive agents modulate DNA methylation status and histone modification via multiple processes and point to additional areas for study of epigenetic mechanisms in skin cancer.

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3-Deazaneplanocin: A new and potent inhibitor of S-adenosylhomocysteine hydrolase and its effects on human promyelocytic leukemia cell line HL-60

Cited by 145 publications

References 15 publications

Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy

Aberrations of EZH2 in Cancer

Epigenetic Cancer Prevention Mechanisms in Skin Cancer

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