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Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer.

Chen K, Wu K, Gormley M, Ertel A, Wang J, Zhang W, Zhou J, Disante G, Li Z, Rui H, Quong AA, McMahon SB, Deng H, Lisanti MP, Wang C, Pestell RG - Oncotarget (2013)

Bottom Line: DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding.DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628.DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.

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p53 and DACH1 regulate common functional gene modules and bind common genes in ChIP-Seq(A-B) Molecular pathways enriched with genes regulated by DACH1 and p53. Pathways enriched with induced genes are represented by red bars. Pathways enriched with repressed genes are represented by green bars. ES score is equal to the confidence of enrichment expressed as –log(p). (C) Number of genes co-regulated by DACH1 and p53. X = genes upregulated by both DACH1 and p53. Y = genes downregulated by both DACH1 and p53. (D) Pie diagram of overlapping genes binding DACH1 and p53 in ChIP-Seq. (E) Cumulative distribution of the location of Chip-Seq peaks with respect to neighboring genes. (F) Histogram of the location of DACH1 and p53 Chip-Seq peaks relative to the transcription start site (TSS) at -10 kb to +50 kb (upper panel) and -1 kb to +1 kb (lower panel). (G) Integrated genome browser visualization of tag density profiles for ChIP-Seq DACH1 and ChIP-Seq p53. Selected genes are PARD6B, par-6 partitioning defective 6 homolog beta and FAM84B, family with sequence similarity 84, member B.
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Figure 1: p53 and DACH1 regulate common functional gene modules and bind common genes in ChIP-Seq(A-B) Molecular pathways enriched with genes regulated by DACH1 and p53. Pathways enriched with induced genes are represented by red bars. Pathways enriched with repressed genes are represented by green bars. ES score is equal to the confidence of enrichment expressed as –log(p). (C) Number of genes co-regulated by DACH1 and p53. X = genes upregulated by both DACH1 and p53. Y = genes downregulated by both DACH1 and p53. (D) Pie diagram of overlapping genes binding DACH1 and p53 in ChIP-Seq. (E) Cumulative distribution of the location of Chip-Seq peaks with respect to neighboring genes. (F) Histogram of the location of DACH1 and p53 Chip-Seq peaks relative to the transcription start site (TSS) at -10 kb to +50 kb (upper panel) and -1 kb to +1 kb (lower panel). (G) Integrated genome browser visualization of tag density profiles for ChIP-Seq DACH1 and ChIP-Seq p53. Selected genes are PARD6B, par-6 partitioning defective 6 homolog beta and FAM84B, family with sequence similarity 84, member B.

Mentions: DACH1-regulated genes identified using gene expression analysis [17] were compared with p53-regulated genes. Three gene expression microarray datasets profiling DACH1 responsive genes were used for analysis (DACH1.0hr, DACH1.18h, DACH1.36h [17], mRNA). The function of genes that are regulated by either DACH1 or p53 were assessed (Fig. 1A,B). Functional enrichment analysis using pathways obtained from the molecular signatures database indicated a set of common pathways regulated by both p53 and DACH1 (Fig. 1A,B). We next examined the proportion of genes regulated by both DACH1 and p53 at serial time points. A total of 242, 2794, and 1621 DACH1-responsive genes were identified from the DACH1.0hr mRNA, DACH1.18h, and DACH1.36h datasets, respectively. Of these genes, 20 out of 242, 129 out of 2794, and 68 out of 1621 were also regulated by p53 (Fig. 1C).


Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer.

Chen K, Wu K, Gormley M, Ertel A, Wang J, Zhang W, Zhou J, Disante G, Li Z, Rui H, Quong AA, McMahon SB, Deng H, Lisanti MP, Wang C, Pestell RG - Oncotarget (2013)

p53 and DACH1 regulate common functional gene modules and bind common genes in ChIP-Seq(A-B) Molecular pathways enriched with genes regulated by DACH1 and p53. Pathways enriched with induced genes are represented by red bars. Pathways enriched with repressed genes are represented by green bars. ES score is equal to the confidence of enrichment expressed as –log(p). (C) Number of genes co-regulated by DACH1 and p53. X = genes upregulated by both DACH1 and p53. Y = genes downregulated by both DACH1 and p53. (D) Pie diagram of overlapping genes binding DACH1 and p53 in ChIP-Seq. (E) Cumulative distribution of the location of Chip-Seq peaks with respect to neighboring genes. (F) Histogram of the location of DACH1 and p53 Chip-Seq peaks relative to the transcription start site (TSS) at -10 kb to +50 kb (upper panel) and -1 kb to +1 kb (lower panel). (G) Integrated genome browser visualization of tag density profiles for ChIP-Seq DACH1 and ChIP-Seq p53. Selected genes are PARD6B, par-6 partitioning defective 6 homolog beta and FAM84B, family with sequence similarity 84, member B.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757249&req=5

Figure 1: p53 and DACH1 regulate common functional gene modules and bind common genes in ChIP-Seq(A-B) Molecular pathways enriched with genes regulated by DACH1 and p53. Pathways enriched with induced genes are represented by red bars. Pathways enriched with repressed genes are represented by green bars. ES score is equal to the confidence of enrichment expressed as –log(p). (C) Number of genes co-regulated by DACH1 and p53. X = genes upregulated by both DACH1 and p53. Y = genes downregulated by both DACH1 and p53. (D) Pie diagram of overlapping genes binding DACH1 and p53 in ChIP-Seq. (E) Cumulative distribution of the location of Chip-Seq peaks with respect to neighboring genes. (F) Histogram of the location of DACH1 and p53 Chip-Seq peaks relative to the transcription start site (TSS) at -10 kb to +50 kb (upper panel) and -1 kb to +1 kb (lower panel). (G) Integrated genome browser visualization of tag density profiles for ChIP-Seq DACH1 and ChIP-Seq p53. Selected genes are PARD6B, par-6 partitioning defective 6 homolog beta and FAM84B, family with sequence similarity 84, member B.
Mentions: DACH1-regulated genes identified using gene expression analysis [17] were compared with p53-regulated genes. Three gene expression microarray datasets profiling DACH1 responsive genes were used for analysis (DACH1.0hr, DACH1.18h, DACH1.36h [17], mRNA). The function of genes that are regulated by either DACH1 or p53 were assessed (Fig. 1A,B). Functional enrichment analysis using pathways obtained from the molecular signatures database indicated a set of common pathways regulated by both p53 and DACH1 (Fig. 1A,B). We next examined the proportion of genes regulated by both DACH1 and p53 at serial time points. A total of 242, 2794, and 1621 DACH1-responsive genes were identified from the DACH1.0hr mRNA, DACH1.18h, and DACH1.36h datasets, respectively. Of these genes, 20 out of 242, 129 out of 2794, and 68 out of 1621 were also regulated by p53 (Fig. 1C).

Bottom Line: DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding.DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628.DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.

ABSTRACT
Breast cancer is a leading form of cancer in the world. The Drosophila Dac gene was cloned as an inhibitor of the hyperactive epidermal growth factor (EGFR), ellipse. Herein, endogenous DACH1 co-localized with p53 in a nuclear, extranucleolar compartment and bound to p53 in human breast cancer cell lines, p53 and DACH1 bound common genes in Chip-Seq. Full inhibition of breast cancer contact-independent growth by DACH1 required p53. The p53 breast cancer mutants R248Q and R273H, evaded DACH1 binding. DACH1 phosphorylation at serine residue (S439) inhibited p53 binding and phosphorylation at p53 amino-terminal sites (S15, S20) enhanced DACH1 binding. DACH1 binding to p53 was inhibited by NAD-dependent deacetylation via DACH1 K628. DACH1 repressed p21CIP1 and induced RAD51, an association found in basal breast cancer. DACH1 inhibits breast cancer cellular growth in an NAD and p53-dependent manner through direct protein-protein association.

Show MeSH
Related in: MedlinePlus