Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer.
Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a ... DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.
Mesh Terms:
Animals, Antineoplastic Agents, Catalytic Domain, Cell Line, Tumor, Cell Movement, Chick Embryo, Chromatin Immunoprecipitation, DNA Damage, DNA-Activated Protein Kinase, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Gene Fusion, Genes, Reporter, HEK293 Cells, Humans, Male, Mass Spectrometry, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, SCID, Models, Molecular, Neoplasm Invasiveness, Oncogene Proteins, Fusion, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Prostatic Neoplasms, Protein Conformation, RNA Interference, Recombinant Fusion Proteins, Time Factors, Transcriptional Activation, Transfection, Tumor Burden, Xenograft Model Antitumor Assays
Animals, Antineoplastic Agents, Catalytic Domain, Cell Line, Tumor, Cell Movement, Chick Embryo, Chromatin Immunoprecipitation, DNA Damage, DNA-Activated Protein Kinase, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Gene Fusion, Genes, Reporter, HEK293 Cells, Humans, Male, Mass Spectrometry, Mice, Mice, Inbred BALB C, Mice, Nude, Mice, SCID, Models, Molecular, Neoplasm Invasiveness, Oncogene Proteins, Fusion, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerases, Prostatic Neoplasms, Protein Conformation, RNA Interference, Recombinant Fusion Proteins, Time Factors, Transcriptional Activation, Transfection, Tumor Burden, Xenograft Model Antitumor Assays
Cancer Cell
Date: May. 17, 2011
PubMed ID: 21575865
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