The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells.

Re-activation of androgen receptor (AR) activity is the main driver for development of castration-resistant prostate cancer. We previously reported that the ubiquitin ligase Siah2 enhanced AR transcriptional activity and prostate cancer cell growth.

Among the genes we found to be regulated by Siah2 was AKR1C3, which encodes a key androgen biosynthetic enzyme implicated in castration-resistant prostate cancer development Here, we found that Siah2 inhibition in CWR22Rv1 prostate cancer cells decreased AKR1C3 expression as well as intracellular androgen levels, concomitant with inhibition of cell growth in vitro and in orthotopic prostate tumors Re-expression of either wild-type or catalytically inactive forms of AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, suggesting a nonenzymatic role for AKR1C3 in these outcomes Unexpectedly, AKR1C3 re-expression in Siah2 knockdown cells elevated Siah2 protein levels, whereas AKR1C3 knockdown had the opposite effect We further found that AKR1C3 can bind Siah2 and inhibit its self-ubiquitination and degradation, thereby increasing Siah2 protein levels We observed parallel expression of Siah2 and AKR1C3 in human prostate cancer tissues Collectively, our findings identify a new role for AKR1C3 in regulating Siah2 stability and thus enhancing Siah2-dependent regulation of AR activity in prostate cancer cells

The Journal of biological chemistry 2015 Jul 09 [Epub]

Lingling Fan, Guihong Peng, Arif Hussain, Ladan Fazli, Emma Guns, Martin Gleave, Jianfei Qi

From the Marlene and Stewart Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201 , From the Marlene and Stewart Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201 , From the Marlene and Stewart Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201, and , the Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada , the Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada , the Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada , From the Marlene and Stewart Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201 

PubMed