Decitabine-induced DNA methylation-mediated transcriptomic reprogramming in human breast cancer cell lines
Ontology highlight
ABSTRACT:
INSTRUMENT(S): DNBSEQ-G400
ORGANISM(S): Homo sapiens
SUBMITTER: Eleftherios Pilalis
PROVIDER: E-MTAB-12224 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Decitabine (DAC), a DNA methyltransferase (DNMT) inhibitor, is tested in combination with conventional anticancer drugs as a treatment option for various solid tumors.
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Project description:Purpose: We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine (DAC) on the proliferation of myeloid leukemia cells in vitro and in vivo, to select the most efficient combination group and explore associated mechanisms of these combination therapies. Experimental Design: After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway. Results: The sequential combination of DAC and IDA showed synergistic induction of cell death in U937, HEL, SKM-1 and cells isolated from AML patients. Importantly, the inhibition of tumor growth in the sequential combination group was found to be significantly higher than that of single drug group or control group in vivo. Moreover, sequential treatment with DAC and IDA induced apoptosis and depression of the Wnt/β-catenin pathway in both culture and animal studies. Conclusions: Our findings showed that sequentially combining decitabine with idarubicin had a synergistic anti-leukemia effect. These findings were attributed to demethylation of Wnt pathway inhibitors and downregulation of Wnt pathway nuclear targets observed in vitro and in vivo. After comparing with five anti-leukemia drugs in several different kinds of cell lines, the combination effect of idarubicin (IDA) with DAC was best. In vivo, by using microPET, TUNEL, and transmission electron microscopy, the inhibitory effects obtained by sequentially combining DAC with IDA, evidenced by evaluating tumor cell proliferation and cell apoptosis. Molecular studies were conducted using gene chip, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry (IHC), used to assess regulation of Wnt/β-catenin pathway.
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Project description:Osteosarcomas are the most common primary malignant tumours of bone, and almost all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. The cell lines showed complex patterns of DNA copy number changes, where copy number gains were significantly associated with gene-rich regions of the genome and losses with gene-poor areas. Integration of the datasets showed that the mRNA levels were regulated by either alterations in DNA copy number or DNA methylation. Using a recurrence threshold of 6/19 (> 30 %) cell lines, 348 genes were identified as having alterations of two data types (gain or hypo-methylation/over-expression, loss or hyper-methylation/under-expression). These genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2M-bM-^@M-^Y-deoxycytidine treatment for all four genes tested. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for some genes. Integrative analysis of genome-wide genetic and epigenetic alterations identified mechanistic dependencies and relationships between DNA copy number and DNA methylation in terms of regulating mRNA expression levels in osteosarcomas, contributing to better understanding of osteosarcoma biology. Comparison of DNA methylation patterns in 19 osteosarcoma cell lines and 6 normal samples (osteoblasts and bones)
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Project description:Osteosarcomas are the most common primary malignant tumours of bone, and almost all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. The cell lines showed complex patterns of DNA copy number changes, where copy number gains were significantly associated with gene-rich regions of the genome and losses with gene-poor areas. Integration of the datasets showed that the mRNA levels were regulated by either alterations in DNA copy number or DNA methylation. Using a recurrence threshold of 6/19 (> 30 %) cell lines, 348 genes were identified as having alterations of two data types (gain or hypo-methylation/over-expression, loss or hyper-methylation/under-expression). These genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2M-bM-^@M-^Y-deoxycytidine treatment for all four genes tested. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for some genes. Integrative analysis of genome-wide genetic and epigenetic alterations identified mechanistic dependencies and relationships between DNA copy number and DNA methylation in terms of regulating mRNA expression levels in osteosarcomas, contributing to better understanding of osteosarcoma biology. Comparison of gene expression patterns in 19 osteosarcoma cell lines and 6 normal samples (osteoblasts and bones)
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