title: Knockdown of AKR1C3 exposes a potential epigenetic susceptibility in prostate cancer cells.
abstract: BACKGROUND
  The aldo-keto reductase 1C3 (AKR1C3) has been heavily implicated in the propagation of prostate malignancy. AKR1C3 protein is elevated within prostate cancer tissue, it contributes to the formation of androgens and downstream stimulation of the androgen receptor (AR). Elevated expression of AKR1C3 is also reported in acute myeloid leukemia but the target nuclear receptors have been identified as members of the peroxisome-proliferator activated receptor (PPARs) subfamily. Thus, AKR1C3 cancer biology is likely to be tissue dependent and hormonally linked to the availability of ligands for both the steroidogenic and non-steroidogenic nuclear receptors.
  
  
  METHODS
  In the current study we investigated the potential for AKR1C3 to regulate the availability of prostaglandin-derived ligands for PPARg mainly, prostaglandin J2 (PGJ2). Using prostate cancer cell lines with stably reduced AKR1C3 levels we examined the impact of AKR1C3 upon proliferation mediated by PPAR ligands.
  
  
  RESULTS
  These studies revealed knockdown of AKR1C3 had no effect upon the sensitivity of androgen receptor independent prostate cancer cells towards PPAR ligands. However, the reduction of levels of AKR1C3 was accompanied by a significantly reduced mRNA expression of a range of HDACs, transcriptional co-regulators, and increased sensitivity towards SAHA, a clinically approved histone deacetylase inhibitor.
  
  
  CONCLUSIONS
  These results suggest a hitherto unidentified link between AKR1C3 levels and the epigenetic status in prostate cancer cells. This raises an interesting possibility of a novel rational to target AKR1C3, the utilization of AKRIC3 selective inhibitors in combination with HDAC inhibition as part of novel epigenetic therapies in androgen deprivation therapy recurrent prostate cancer.
authors.affiliation: Centre for Endocrinology Diabetes & Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Edgbaston B15 2TT, UK. Electronic address: c.l.doig@bham.ac.uk.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Doig
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Battaglia
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK.
authors.forename: Farhat L
authors.initials: FL
authors.lastname: Khanim
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, B15 2TT, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bunce
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Moray J
authors.initials: MJ
authors.lastname: Campbell
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D000077337:Vorinostat
chemical_list: C410798:AR protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047495:PPAR gamma; D011944:Receptors, Androgen; D000077337:Vorinostat; C037112:9-deoxy-delta-9-prostaglandin D2; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; D015230:Prostaglandin D2
keywords: 17B-Hydroxysteroid dehydrogenase; AKR1C3; Bezafibrate; PPAR; Prostaglandins; Prostate cancer