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Genomic analysis of DNA repair genes and androgen signaling in prostate cancer.
Jividen, Kasey; Kedzierska, Katarzyna Z; Yang, Chun-Song; Szlachta, Karol; Ratan, Aakrosh; Paschal, Bryce M.
Afiliación
  • Jividen K; Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
  • Kedzierska KZ; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Yang CS; Center for Cell Signaling, University of Virginia, Charlottesville, VA, USA.
  • Szlachta K; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
  • Ratan A; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Paschal BM; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
BMC Cancer ; 18(1): 960, 2018 Oct 10.
Article en En | MEDLINE | ID: mdl-30305041
ABSTRACT

BACKGROUND:

The cellular effects of androgen are transduced through the androgen receptor, which controls the expression of genes that regulate biosynthetic processes, cell growth, and metabolism. Androgen signaling also impacts DNA damage signaling through mechanisms involving gene expression and transcription-associated DNA damaging events. Defining the contributions of androgen signaling to DNA repair is important for understanding androgen receptor function, and it also has translational implications.

METHODS:

We generated RNA-seq data from multiple prostate cancer lines and used bioinformatic analyses to characterize androgen-regulated gene expression. We compared the results from cell lines with gene expression data from prostate cancer xenografts, and patient samples, to query how androgen signaling and prostate cancer progression influences the expression of DNA repair genes. We performed whole genome sequencing to help characterize the status of the DNA repair machinery in widely used prostate cancer lines. Finally, we tested a DNA repair enzyme inhibitor for effects on androgen-dependent transcription.

RESULTS:

Our data indicates that androgen signaling regulates a subset of DNA repair genes that are largely specific to the respective model system and disease state. We identified deleterious mutations in the DNA repair genes RAD50 and CHEK2. We found that inhibition of the DNA repair enzyme MRE11 with the small molecule mirin inhibits androgen-dependent transcription and growth of prostate cancer cells.

CONCLUSIONS:

Our data supports the view that crosstalk between androgen signaling and DNA repair occurs at multiple levels, and that DNA repair enzymes in addition to PARPs, could be actionable targets in prostate cancer.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / ADN de Neoplasias / Receptores Androgénicos / Reparación del ADN / Andrógenos Límite: Animals / Humans / Male Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / ADN de Neoplasias / Receptores Androgénicos / Reparación del ADN / Andrógenos Límite: Animals / Humans / Male Idioma: En Revista: BMC Cancer Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos