DNA methylation analysis of the tumor suppressor gene CDKN2B in Brazilian leukemia patients

Lima, Patricia Santos Pereira; Molffeta, Greice Andreoti; Araújo, Astolfo Gomes de Mello; Zago, Marco Antônio; Silva, Wilson A.

doi:10.1590/s1415-47572008000400005

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…In MDS BM-CD33 cells these mechanisms involve the Cyclin D2, CDK4 and CDK6 proteins, whereas in AML cells the mechanisms are dependent on p15. This hypothesis is supported by published data showing p15 is one of the genes most frequently inactivated in leukaemic patients by DNA methylation and that p15 methylation in AML patients is associated with poor prognosis [40], [41].…”

Section: Discussionsupporting

confidence: 54%

“…In THP1 the effect of vorinostat on the expression of most of these genes was less pronounced than in K562 and HL60. Interestingly, some genes, such as p15 (Figure 4A, 1), and Cyclin D1 (Figure 4A, 2), often deregulated in MDS and AML and associated with worse prognosis [7], [40], [41], [42], were modulated to a greater extent in HL60, whereas AXL (Figure 4A, 1), frequently up-regulated in AML and associated with adverse prognosis [30], was more marked in K562.…”

Section: Resultsmentioning

confidence: 99%

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Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

et al. 2013

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BackgroundAberrant epigenetic patterns are central in the pathogenesis of haematopoietic diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Vorinostat is a HDACi which has produced responses in these disorders. The purpose of this study was to address the functional effects of vorinostat in leukemic cell lines and primary AML and MDS myeloid cells and to dissect the genetic and molecular mechanisms by which it exerts its action.Methodology/Principal FindingsFunctional assays showed vorinostat promoted cell cycle arrest, inhibited growth, and induced apoptosis and differentiation of K562, HL60 and THP-1 and of CD33+ cells from AML and MDS patients. To explore the genetic mechanism for these effects, we quantified gene expression modulation by vorinostat in these cells. Vorinostat increased expression of genes down-regulated in MDS and/or AML (cFOS, COX2, IER3, p15, RAI3) and suppressed expression of genes over-expressed in these malignancies (AXL, c-MYC, Cyclin D1) and modulated cell cycle and apoptosis genes in a manner which would favor cell cycle arrest, differentiation, and apoptosis of neoplastic cells, consistent with the functional assays. Reporter assays showed transcriptional effect of vorinostat on some of these genes was mediated by proximal promoter elements in GC-rich regions. Vorinostat-modulated expression of some genes was potentiated by mithramycin A, a compound that interferes with SP1 binding to GC-rich DNA sequences, and siRNA-mediated SP1 reduction. ChIP assays revealed vorinostat inhibited DNA binding of SP1 to the proximal promoter regions of these genes. These results suggest vorinostat transcriptional action in some genes is regulated by proximal promoter GC-rich DNA sequences and by SP1.ConclusionThis study sheds light on the effects of vorinostat in AML and MDS and supports the implementation of clinical trials to explore the use of vorinostat in the treatment of these diseases.

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Section: Discussionsupporting

confidence: 54%

Section: Resultsmentioning

confidence: 99%

Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

et al. 2013

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“…Another study demonstrated that folic acid prevents NTDs by partially reducing or reversing aberrant DNA methylation via the one‐carbon metabolic pathway (Blom et al, 2006). The DNA methylation state is maintained primarily by DNMTs, which catalyze the transfer of a methyl group from the methyl precursor, SAM, onto the 5‐position of certain cytosines in CpG dinucleotides (Lima et al, 2008). DNA methylation is an epigenetic event that plays an important role in regulating gene function.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress is implicated in arsenic‐induced neural tube defects in chick embryos

Han

Song

Cui

et al. 2011

Intl J of Devlp Neuroscience

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The potential of arsenic to induce neural tube defects (NTDs) remains a topic of controversy. In our previous study, oxidative stress and altered DNA methylation were observed in arsenic-exposed animal models. However, the correlation between these conditions was not fully understood. Therefore, our present aim was to determine whether arsenic exposure results in altered reactive oxygen species levels that affect DNA methylation and may contribute to NTDs in chick embryos. We demonstrated that arsenic-induced NTDs were associated with oxidative stress. Increased intracellular oxidative species and DNA methylation changes were observed following arsenic exposure. These changes were accompanied by a decrease in manganese superoxide dismutase activity. Furthermore, a significant decrease in DNA methyltransferase (DNMT) 1 and 3a expression was observed following arsenic exposure. The known antioxidant N-acetyl-l-cysteine, a known antioxidant, ameliorated global DNA hypomethylation and the decreased DNMT 1 and 3a expression observed during arsenic exposure. In addition, arsenic caused a significant decrease in S-adenosylmethionine (SAM) and significant increase in S-adenosylhomocysteine (SAH). This effect resulted in a significant reduction of the SAM/SAH ratio, which may also contribute to DNA hypomethylation. In conclusion, oxidative stress and reduction in SAM/SAH ratio during arsenic exposure in chick embryos seem to modulate DNA methylation and contribute to arsenic-induced NTDs via epigenetic mechanisms.

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“…It encodes both the ARF protein, which binds the p53-stabilizing protein MDM2, and the INK4 protein, a cyclin-dependent kinase inhibitor. Loss-of-function mutations in CDKN2A are responsible for familiar forms of human melanoma (LIMA et al 2008;HELL-STRÖM et al 2010).…”

mentioning

confidence: 99%

DNA Methylation Analysis of the Gene CDKN2B in Gallus gallus (Chicken)

Gryzińska

Andraszek²,

Jocek³

2013

folia biol (krakow)

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GRYZIÑSKA M., ANDRASZEK K., G. JOCEK. 2013. DNA methylation analysis of the gene CDKN2B in Gallus gallus (chicken). Folia Biologica (Kraków) 61: 165-171.Methylation is an epigenetic modification of DNA affecting gene expression without changing the structure of nucleotides. It plays a crucial role in the embryonic and post-embryonic development of living organisms. Methylation level is tissue and species-specific and changes with age. The study was aimed at identifying the methylation of the CDKN2B gene situated at locus bar in Polbar chickens on the 6 JD and 18 JD day of embryonic development using the MSP (methylation-specific PCR) method. Methylation was not detected in the promoter region of gene CDKN2B on the 6 JD and 18 JD day of embryonic development. As one of the five genes responsible for melanine activity in melanocytes and highly active, it can contribute to the production of this pigment. The present research broadens the current knowledge of the chicken epigenome and the mechanism of autosexing in birds.

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DNA methylation analysis of the tumor suppressor gene CDKN2B in Brazilian leukemia patients

Cited by 5 publications

References 26 publications

Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

Oxidative stress is implicated in arsenic‐induced neural tube defects in chick embryos

DNA Methylation Analysis of the Gene CDKN2B in Gallus gallus (Chicken)

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