Chromatin, cancer and drug therapies

Cortez, Connie C.; Jones, Peter A.

doi:10.1016/j.mrfmmm.2008.07.006

Cited by 72 publications

(49 citation statements)

References 120 publications

(119 reference statements)

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“…Our functional analyses were mainly based on in vitro models, so additional data from animal experimental models may reinforce the importance of JMJD2B as a therapeutic target in human cancer. Recently, inhibitors targeting DNA methyltransferases and histone deacetylases were approved by the FDA to use for patients with hematologic malignancies (40,41). Furthermore, a novel inhibitor targeting the histone demethylase LSD1 has been developed and a suppressive effect on tumor growth, via reexpression of epigenetically silenced genes in colon cancer cells, was shown (42).…”

Section: Discussionmentioning

confidence: 99%

The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6

Toyokawa

Cho

Iwai

et al. 2011

Cancer Prevention Research

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Histone methyltransferases and demethylases are known to regulate transcription by altering the epigenetic marks on histones, but the pathologic roles of their dysfunction in human diseases, such as cancer, still remain to be elucidated. Herein, we show that the histone demethylase JMJD2B is involved in human carcinogenesis. Quantitative real-time PCR showed notably elevated levels of JMJD2B expression in bladder cancers, compared with corresponding nonneoplastic tissues (P < 0.0001), and elevated protein expression was confirmed by immunohistochemistry. In addition, cDNA microarray analysis revealed transactivation of JMJD2B in lung cancer, and immunohistochemical analysis showed protein overexpression in lung cancer. siRNA-mediated reduction of expression of JMJD2B in bladder and lung cancer cell lines significantly suppressed the proliferation of cancer cells, and suppressing JMJD2B expression lead to a decreased population of cancer cells in S phase, with a concomitant increase of cells in G 1 phase. Furthermore, a clonogenicity assay showed that the demethylase activity of JMJD2B possesses an oncogenic activity. Microarray analysis after knockdown of JMJD2B revealed that JMJD2B could regulate multiple pathways which contribute to carcinogenesis, including the cell-cycle pathway. Of the downstream genes, chromatin immunoprecipitation showed that CDK6 (cyclin-dependent kinase 6), essential in G 1 -S transition, was directly regulated by JMJD2B, via demethylation of histone H3-K9 in its promoter region. Expression levels of JMJD2B and CDK6 were significantly correlated in various types of cell lines. Deregulation of histone demethylation resulting in perturbation of the cell cycle, represents a novel mechanism for human carcinogenesis and JMJD2B is a feasible molecular target for anticancer therapy. Cancer Prev Res; 4(12); 2051-61. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6

Toyokawa

Cho

Iwai

et al. 2011

Cancer Prevention Research

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“…To date, there are many types of demethylating agents that have been shown to inhibit promoter methylation and reactivate silenced genes [4][5][6]. Some of these have been approved or are in clinical studies to be developed as cancer drugs [7].The cytosine analog 5-aza-2'-deoxycytidine (5azadC), also known as decitabine, has been widely used as a DNA methyltransferase (Dnmt) inhibitor to reverse aberrant hypermethylation [8,9]. It has been approved for hematological malignancies, showing favorable results with low dose treatment [10,11].…”

mentioning

confidence: 99%

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confidence: 99%

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

et al. 2010

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Abstract. The DNA methyltransferase (Dnmt) inhibitor and demethylating agent 5-aza-2'-deoxycytidine (5azadC) has been used to induce cellular differentiation and gene activation. It has been approved for treating several kinds of malignancies due to its ability to reactivate silenced tumor suppressor genes. Considering the potential effect of 5azadC on non-targeted genomic regions in normal cells, we investigated its effect on repetitive sequences and selected gene loci, Sall3, Per1, Clu, Dpep1 and Igf2r, including tissue-dependent and differentially methylated regions, by treating mouse NIH/3T3 fibroblast cells with concentrations of 5azadC ranging from 0.001 to 5 μM. Demethylation of minor satellite repeats and endogenous viruses was concentration dependent, and the demethylation was strong at 1 and 5 μM. In genic regions, the methylation level decreased only at 0.1 μM, but was minimally altered at concentrations lower or higher, regardless of the abundance of CpG sites. Thus, repeats are strongly demethylated, but genic regions are only demethylated at effective doses. Genes were activated by 5azadC treatment and were accompanied by a unique combination of histone modifications in genic regions, including an increased level of H3K9me3 and a decreased level of AcH3. Increase of H3K9me3 in genic regions was not observed in Dnmt knock out cells. We identified differential effects of 5azadC on repetitive sequences and genic regions and revealed the importance of choosing appropriate 5azadC doses to achieve targeted gene recovery. Key words: 5-aza-2'-deoxycytidine, Decitabine, DNA methylation, Epigenetics, Histone modification (J. Reprod. Dev. 56: [86][87][88][89][90][91][92][93] 2010) NA methylation is one of the epigenetic events associated with gene regulation and function. Hypermethylation of promoter regions of tumor suppressor genes causes silencing of the genes that lead to cancer [1][2][3]. Thus, reversing the methylation status of gene promoters to their prevalent methylation states has become a treatment option for certain cancer types. To date, there are many types of demethylating agents that have been shown to inhibit promoter methylation and reactivate silenced genes [4][5][6]. Some of these have been approved or are in clinical studies to be developed as cancer drugs [7].The cytosine analog 5-aza-2'-deoxycytidine (5azadC), also known as decitabine, has been widely used as a DNA methyltransferase (Dnmt) inhibitor to reverse aberrant hypermethylation [8,9]. It has been approved for hematological malignancies, showing favorable results with low dose treatment [10,11]. Known to have dual modes of action, 5azadC at low doses induces gene hypomethylation, whereas high doses of 5azadC induce cytotoxicity and cause severe side effects in patients [12,13].Nearly 40% of the mouse genome is composed of repetitive sequences including different classes of interspersed repeats, such as LINEs, SINEs, LTR elements and satellites, that are mainly found in heterochromatin regions [14]. Most repeats are densely m...

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“…However, the molecular mechanisms for drug response in these patients have not been determined yet. Several other HDAC inhibitors such as depsipeptide and phenylbutyrate are also under clinical trials [99].…”

Section: Cancer Epigenomicsmentioning

confidence: 99%

The Contribution of Next Generation Sequencing Technologies to Epigenome Research of Stem Cell and Tumorigenesis

Li¹

2013

Human Genet Embryol

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Epigenome contains another layer of genetic information, not as stable as genome. Dynamic epigenome can serve as an interface to explain the role of environmental factors. Stem cell and tumorigenesis are reported to be closely associated with epigenome modifications. Next generation sequencing (NGS) technologies have directly leaded to the recent advances in epigenome research of stem cell and cancer. DNA methylation and histone modification are two major epigenetic modifications. Four NGS-based approaches have been developed to identify these two epigenetic modifications, including whole genome bisulfite sequencing (WGBS), methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq), reduced representation bisulfite sequencing (RRBS) and chromatin immunoprecipitation sequencing (ChIP-Seq). This paper reviews the recent advances of WGBS, MeDIP-Seq and RRBS for DNA methylation and ChIP-Seq for histone modification in the field of stem cell. The potential contribution of epigenetic modifications to tumorigenesis is also described. At present, the epigenome research still faces the defects of current sampling strategy and unknown network regulation pattern. In future, worldwide collaboration and latest sequencing technologies application are expected to solve these problem and offer new insight into epigenome research.

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Chromatin, cancer and drug therapies

Cited by 72 publications

References 120 publications

The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6

The Histone Demethylase JMJD2B Plays an Essential Role in Human Carcinogenesis through Positive Regulation of Cyclin-Dependent Kinase 6

Resistance to 5-aza-2'-deoxycytidine in Genic Regions Compared to Non-genic Repetitive Sequences

The Contribution of Next Generation Sequencing Technologies to Epigenome Research of Stem Cell and Tumorigenesis

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