Selective AR Modulators that Distinguish Proliferative from Differentiative Gene Promoters
Technical Report,30 Jul 2014,29 Jul 2018
University of Michigan Medical School Ann Arbor United States
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Our goal was to identify via a high-throughput screen compounds that inhibit androgen receptor AR target genes driving cancer but not normal cell growth. We hypothesized that genes with consensus response elements cAREs would drive proliferation but genes with selective response elements sAREs would drive differentiation. Doxorubicin showed this activity by acting on DNA rather than directly with AR, as shown by protein-DNA interaction assays. The differential effect of dox was obtained at low dose, in multiple prostate cancer cell lines, and shown in vivo by chromatin immunoprecipitation ChIP studies. ChIP-seq provided a global view of genes responsive to low dox treatment in LNCaP cells. Binding to cAREs decreased with increasing dox concentration. For a subset of genes at low dox, AR binding increased at pre-existing sites overlapping sites for prostate-specific factors, such as FOXA1. The transcriptome viewed by RNA-seq revealed cell cycle genes to be downregulated by low dox and DNA damage response increased by high dox. The differential effect occurred in xenograft tumors notably at the level of gene expression. Thus doxorubicin provides proof of our hypothesis and unique opportunities for prostate cancer treatment.
- Medicine and Medical Research
- Genetic Engineering and Molecular Biology