Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer
Copyright policy )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.
Male, Cancer Research, Chromatin Immunoprecipitation, Mice, Nude, Antineoplastic Agents, Chick Embryo, DNA-Activated Protein Kinase, Mass Spectrometry, Mice, Cell Movement, Genes, Reporter, Catalytic Domain, Cell Line, Tumor, Animals, Humans, Enzyme Inhibitors, Mice, Inbred BALB C, Cell Biology, Gene Expression Regulation, Neoplastic, HEK293 Cells, Oncology, Gene Fusion, DNA Damage
Male, Cancer Research, Chromatin Immunoprecipitation, Mice, Nude, Antineoplastic Agents, Chick Embryo, DNA-Activated Protein Kinase, Mass Spectrometry, Mice, Cell Movement, Genes, Reporter, Catalytic Domain, Cell Line, Tumor, Animals, Humans, Enzyme Inhibitors, Mice, Inbred BALB C, Cell Biology, Gene Expression Regulation, Neoplastic, HEK293 Cells, Oncology, Gene Fusion, DNA Damage
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