Project description:We have used chromatin immune-precipitation with parallel sequencing (ChIP-Seq) technology to identify genome-wide p53 binding in human lymphoblastoid cell lines treated with a DNA-damaging chemotherapeutic reagent doxorubicin. ChIP-Seq analysis of p53 binding sites in human lymphoblastoid cells treated with Doxorubicin or vehicle

2013-10-23 | E-GEOD-46991 | biostudies-arrayexpress

Deficiency in tumor suppressor p53 is required for doxorubicin induced transcriptional upregulation of NF-kB target genes in human breast cancer

Project description:NF-kB has been linked to doxorubicin-based chemotherapy resistance in breast cancer patients. NF-kB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined, however its functional consequences in terms the spectrum of NF-kB -dependent genes expressed and, thus, the impact on tumour cell behaviour are unclear. We hypothesized that NF-kB gene expression profile induced by doxorubicin might be different among breast cancer cells and tumors. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-kB driven-gene transcription demonstrated by gene expression microarrays. Selected genes (ICAM-1, CXCL1, IL8) related with invasion, metastasis and chemoresistance expression were confirmed by RT-PCR in a subset of additional doxorubicin-treated cells and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of these NF-kB targeted genes. Overexpression of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-kB driven transcription induced by doxorubicin. Moreover, tumors with a p53 deficient background and nuclear NF-kB /p65 expression correlated with reduced disease free-survival. This study supports that tumor molecular profiles for doxorubicin driven NF-kB-response are likely to exist. A link between p53 deficiency and the presence of active transcriptionally NF-kB could favour an aggressive behaviour and might have implications for doxorubicin-based chemotherapy in breast tumors exhibiting aberrant p53 activity 12 samples were analyzed: controls (n=3); Doxorubicin treated (n=3); MLN120B treated (n=3); MLN120B + Doxorubicin treated (n=3)

2013-12-31 | E-GEOD-47013 | biostudies-arrayexpress

Detoxifying doxorubicin

Project description:The anthracycline doxorubicin is a highly effective anti-cancer drug associated with severe side effects, including secondary tumors and cardiotoxicity. Doxorubicin induces DNA damage through double-strand breaks (DSBs) and epigenetic or chromatin damage through histone eviction. We examined whether separation of these activities can help to detoxify doxorubicin, while maintaining its chemotherapeutic efficacy. We show that anthracycline variants harboring the histone eviction activity alone remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and secondary tumor formation. We thus demonstrate that treatment-limited side effects of doxorubicin can be synthesized away, yielding effective chemotherapeutics towards improved and prolonged treatment responses and higher patient quality of life.

2019-09-01 | GSE108179 | GEO

Genome-wide map of p53 binding sites by ChIP-seq in human lymphoblastoid cell lines treated with doxorubicin

2013-10-23 | GSE46991 | GEO

Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells (Affymetrix)

Project description:The effects of diverse stresses on promoter selectivity and transcription regulation by the tumor suppressor p53 are poorly understood. We have taken a comprehensive approach to characterizing the human p53 network that includes p53 levels, binding, expression and chromatin changes under diverse stresses. Human osteosarcoma U2OS cells treated with anti-cancer drugs Doxorubicin or Nutlin-3 led to strikingly different p53 gene binding patterns based on ChIP-seq experiments. While two contiguous RRRCWWGYYY decamers is the consensus binding motif, p53 can bind a single decamer and function in vivo. Although the number of sites bound by p53 was 6-times greater for Nutlin-3 than Doxorubicin, expression changes induced by Nutlin-3 were much less dramatic compared to Doxorubicin. Unexpectedly, the solvent DMSO alone induced p53 binding to many sites common to Doxorubicin; however, this binding had no effect on target gene expression. Together, these data imply a two-stage mechanism for p53 transactivation where p53 binding only constitutes the first stage. Furthermore, both p53 binding and transactivation were associated with increased active histone modification H3K4me3. We discovered 149 putative new p53 target genes including several that are relevant to tumor suppression, revealing potential new targets for cancer therapy and expanding our understanding of the p53 regulatory network. Gene expression analysis (using Affymetrix Human Genome U133 Plus 2.0 GeneChipÂ® arrays) of the p53 response in U2OS cells treated with either Doxorubicin or Nutlin-3, relative to their controls No Treatment and DMSO, respectively.

2013-07-01 | E-GEOD-46493 | biostudies-arrayexpress

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