Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia

Yun, Haiyang; Damm, Frédérik; Yap, Damian; Schwarzer, Adrian; Chaturvedi, Anuhar; Jyotsana, Nidhi; Lübbert, Michael; Bullinger, Lars; Döhner, Konstanze; Geffers, Robert; Aparicio, Samuel; Humphries, R. Keith; Ganser, Arnold; Heuser, Michael

doi:10.3324/haematol.2013.101386

Cited by 24 publications

(18 citation statements)

References 52 publications

(54 reference statements)

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“…Indeed, the initial patterns of gene expression in patients treated with decitabine may influence the efficacy of this drug. For example, patients with low levels of lysine methyltransferase MLL5 were developing resistance to low‐doses of decitabine . In addition, expression levels of two enzymes involved in decitibine metabolism, namely cytidine deaminase and deoxycytidine kinase, differ between non‐responders and responders .…”

Section: Discussionmentioning

confidence: 99%

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

Beetch

Lubecka

Shen

et al. 2019

Molecular Nutrition Food Res

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Scope Loci‐specific increase in DNA methylation occurs in cancer and may underlie gene silencing. It is investigated whether dietary stilbenoids, resveratrol, and pterostilbene exert time‐dependent effects on DNA methylation patterns and specifically methylation‐silenced tumor suppressor genes in breast cancer cells. Methods and results Following genome‐wide DNA methylation analysis with Illumina‐450K, changes characteristic of early and late response to stilbenoids are identified. Interestingly, often the same genes but at different CpG loci, the same gene families, or the same functional gene categories are affected. CpG loci that lose methylation in exposed cells correspond to genes functionally associated with cancer suppression. There is a group of genes, including SEMA3A, at which the magnitude of hypomethylation in response to stilbenoids rises with increasing invasive potential of cancer cells. Decreased DNA methylation at SEMA3A promoter and concomitant gene upregulation coincide with increased occupancy of active histone marks. Open chromatin upon exposure to stilbenoids may be linked to decreased DNMT3A binding followed by increased NF1C transcription factor occupancy. Sequestration of DNMT3A is possibly a result of stilbenoid‐mediated increase in SALL3 expression, which was previously shown to bind and inhibit DNMT3A activity. Conclusions The findings define mechanistic players in stilbenoid‐mediated epigenetic reactivation of genes suppressing cancer.

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Section: Discussionmentioning

confidence: 99%

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

Beetch

Lubecka

Shen

et al. 2019

Molecular Nutrition Food Res

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“…Set3 complex (Set3C) was also recently tied to the DNA damage response operating under a model of altered histone acetylation dynamics ( Torres-Machorro et al 2015 ). MLL5 in mammals has been tied to several different cellular processes, including hematopoesis ( Heuser et al 2009 ; Madan et al 2009 ; Zhang et al 2009 ), cell cycle progression ( Deng et al 2004 ; Cheng et al 2008 ), oncogenesis ( Emerling et al 2002 ), and DNA methylation ( Yun et al 2014 ), though its exact mechanistic role or binding partners in these diverse functions have not been fully resolved. In Drosophila , upSET e00365/e00365 flies were described to be viable, but with a female fertility defect due to derepression of transposable elements in the ovary ( Rincon-Arano et al 2012 ).…”

mentioning

confidence: 99%

upSET, the Drosophila homologue of SET3, Is Required for Viability and the Proper Balance of Active and Repressive Chromatin Marks

McElroy

Jung

Zee

et al. 2017

G3 Genes|Genomes|Genetics

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Chromatin plays a critical role in faithful implementation of gene expression programs. Different post-translational modifications (PTMs) of histone proteins reflect the underlying state of gene activity, and many chromatin proteins write, erase, bind, or are repelled by, these histone marks. One such protein is UpSET, the Drosophila homolog of yeast Set3 and mammalian KMT2E (MLL5). Here, we show that UpSET is necessary for the proper balance between active and repressed states. Using CRISPR/Cas-9 editing, we generated S2 cells that are mutant for upSET. We found that loss of UpSET is tolerated in S2 cells, but that heterochromatin is misregulated, as evidenced by a strong decrease in H3K9me2 levels assessed by bulk histone PTM quantification. To test whether this finding was consistent in the whole organism, we deleted the upSET coding sequence using CRISPR/Cas-9, which we found to be lethal in both sexes in flies. We were able to rescue this lethality using a tagged upSET transgene, and found that UpSET protein localizes to transcriptional start sites (TSS) of active genes throughout the genome. Misregulated heterochromatin is apparent by suppressed position effect variegation of the wm4 allele in heterozygous upSET-deleted flies. Using nascent-RNA sequencing in the upSET-mutant S2 lines, we show that this result applies to heterochromatin genes generally. Our findings support a critical role for UpSET in maintaining heterochromatin, perhaps by delimiting the active chromatin environment.

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“…Previous studies have found that tumorigenesis and the metastasis of esophageal cancer result from the downregulation of the expression of multiple tumor suppressor genes and the abnormal hypermethylation of their promoters ( 33 – 35 ). Studies have shown that 5-azacytidine, a clinical chemotherapeutic drug used in the treatment of various types of cancer, inhibits the methylation of the promoter of multiple genes and affects the expression of these genes ( 39 , 40 ). In this study, we used EC9706 cells to assess the anticancer effects of 5-azacytidine in esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1

Niu

et al. 2016

International Journal of Molecular Medicine

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5-Azacytidine is a well-known anticancer drug that is clinically used in the treatment of breast cancer, melanoma and colon cancer. It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells. However, corresponding mechanisms remain unclear. In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17). Moreover, the inhibition of the metastasis of the 5-azacytidine-treated EC9706 cells was impaired following transfection with siRNA targeting CDH1 (CDH1 siRNA), and the inhibition of cell proliferation was attenuated following the downregulation of SOX17 by siRNA targeting SOX17 (SOX17 siRNA). Furthermore, 5-azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter. The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17. The expression levels of CDH1 and SOX17 negatively correlate with the promoter methylation levels. CDH1 and SOX17 are potential indicators of the clinical application of 5-azacytidine.

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Impact of MLL5 expression on decitabine efficacy and DNA methylation in acute myeloid leukemia

Cited by 24 publications

References 52 publications

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

upSET, the Drosophila homologue of SET3, Is Required for Viability and the Proper Balance of Active and Repressive Chromatin Marks

5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1

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