Abstract
BackgroundThe 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.MethodsWe 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.ResultsOur 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.ConclusionsOur 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.
Highlights
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
Prostate cancer cell line models contain potential deleterious mutations in the DNA repair machinery We set out to define the state of the DNA repair machinery in prostate cancer cell lines, including how it is influenced by androgen signaling
A potential difficulty of comparing androgen signaling across prostate cancer cells is - depending on the line - the androgen receptor (AR) is mutated, alternatively spliced, and expressed at different levels, all of which could affect the transcriptional output measured in response to androgen [44, 45]
Summary
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. Prostate cancer remains the most commonly diagnosed cancer in men, with a lifetime risk of approximately 1 in 7 [1, 2]. Both cancer-associated events and the normal physiology of prostate involve signaling through the androgen receptor (AR) [3]. CRPC is characterized by changes in growth factor-, cell surface receptor-, and DNA repair enzymes have emerged as actionable targets for cancer, including prostate cancer. The data from clinical trials has shown that inhibiting the DNA repair enzyme PARP-1 in ovarian, breast, and prostate cancers improves outcome in patients that have genetic alterations in other components of the DNA repair machinery [6,7,8]. It has been shown that treating prostate cancer xenografts with inhibitors to AR (bicalutimide) and PARP-1 (Olaparib) inhibits tumor growth [12]
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