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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes (methylation)

ABSTRACT: A combinatorial treatment consisting of a DNMTi and a LSD1i shows synergistic effects in reactivating aberrantly silenced genes by enriching H3K4me2 and H3K4me.

ORGANISM(S): Homo sapiens

PROVIDER: GSE41525 | GEO | 2013/08/01

SECONDARY ACCESSION(S): PRJNA177920

REPOSITORIES: GEO

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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes (methylation)

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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes (gene expression)

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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes (gene expression)

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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Combinatorial treatment of DNMT inhibitor and LSD1 inhibitor results in cell growth inhibition and reexpression of epigenetically silenced genes

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Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes.

Project description:Abnormal DNA CpG island hypermethylation and transcriptionally repressive histone modifications are associated with the aberrant silencing of tumor suppressor genes. Lysine methylation is a dynamic, enzymatically controlled process. Lysine-specific demethylase 1 (LSD1) has recently been identified as a histone lysine demethylase. LSD1 specifically catalyzes demethylation of mono- and dimethyl-lysine 4 of histone 3 (H3K4), key positive chromatin marks associated with transcriptional activation. We hypothesized that a novel class of oligoamine analogues would effectively inhibit LSD1 and thus cause the reexpression of aberrantly silenced genes.Human colorectal cancer cells were treated with the oligoamines and changes in mono- and dimethyl-H3K4 and other chromatin marks were monitored. In addition, treated cells were evaluated for the reexpression of the aberrantly silenced secreted frizzled-related proteins (SFRP) Wnt signaling pathway antagonist genes. Finally, the effects of the LSD1 inhibitors were evaluated in an in vivo xenograft model.Treatment of HCT116 human colon adenocarcinoma cells in vitro resulted in increased H3K4 methylation and reexpression of silenced SFRP genes. This reexpression is also accompanied by a decrease in H3K9me2 repressive mark. Importantly, cotreatment with low doses of oligoamines and a DNA methyltransferase inhibitor highly induces the reexpression of the aberrantly silenced SFRP2 gene and results in significant inhibition of the growth of established tumors in a human colon tumor model in vivo.The use of LSD1-inhibiting oligoamine analogues in combination with DNA methyltransferase inhibitors represents a highly promising and novel approach for epigenetic therapy of cancer.

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Project description:Transcriptional silencing associated with aberrant promoter hypermethylation is a common mechanism of inactivation of tumor suppressor genes in cancer cells. To globally profile the genes silenced by hypermethylation in prostate cancer, we screened a whole genome expression microarray for genes reactivated in the LNCaP, DU-145, PC-3, and MDA2b prostate tumor cell lines after treatment with the demethylating drug 5-aza-2-deoxycytidine and the histone deacetylation-inhibiting drug trichostatin A. A total of 2,997 genes showed at least 2-fold upregulation of expression after drug treatment in at least one prostate tumor cell line. For validation, we examined the first 45 genes, ranked by upregulation of expression, which had a typical CpG island and were known to be expressed in the normal cell counterpart. Two important findings were, first, that several genes known to be frequently hypermethylated in prostate cancer were apparent, and, second, that validation studies revealed eight novel genes hypermethylated in the prostate tumor cell lines, four of which were unmethylated in normal prostate cells and hypermethylated in primary prostate tumors (SLC15A3, 66%; KRT7, 54%; TACSTD2, 17%; GADD45b, 3%). Thus, we established the utility of our screen for genes hypermethylated in prostate cancer cells. One of the novel genes was TACSTD2/TROP2, a marker of human prostate basal cells with stem cell characteristics. TACSTD2 was unmethylated in prostatic intraepithelial neoplasia and may have utility in emerging methylation-based prostate cancer tests. Further study of the hypermethylome will provide insight into the biology of the disease and facilitate translational studies in prostate cancer.

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