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Lookup NU author(s): Dr Kelly Coffey, Lynsey Rogerson, Claudia Ryan-Munden, Dhuha Alkharaif, Dr Jacqueline Stockley, Professor Rakesh Heer, Dr Kanagasabai Sahadevan, Daniel O'Neill, Dominic Jones, Dr Steven Darby, Dr Luke GaughanORCiD, Professor Craig Robson
The androgen receptor (AR) is a key molecule involved in prostate cancer (PC) development and progression. Post-translational modification of the AR by co-regulator proteins can modulate its transcriptional activity. To identify which demethylases might be involved in AR regulation, an siRNA screen was performed to reveal that the demethylase, KDM4B, may be an important co-regulator protein. KDM4B enzymatic activity is required to enhance AR transcriptional activity; however, independently of this activity, KDM4B can enhance AR protein stability via inhibition of AR ubiquitination. Importantly, knockdown of KDM4B in multiple cell lines results in almost complete depletion of AR protein levels. For the first time, we have identified KDM4B to be an androgen-regulated demethylase enzyme, which can influence AR transcriptional activity not only via demethylation activity but also via modulation of ubiquitination. Together, these findings demonstrate the close functional relationship between AR and KDM4B, which work together to amplify the androgen response. Furthermore, KDM4B expression in clinical PC specimens positively correlates with increasing cancer grade (P < 0.001). Consequently, KDM4B is a viable therapeutic target in PC.
Author(s): Coffey K, Rogerson L, Ryan-Munden C, Alkharaif D, Stockley J, Heer R, Sahadevan K, O'Neill D, Jones D, Darby S, Staller P, Mantilla A, Gaughan L, Robson CN
Publication type: Article
Publication status: Published
Journal: Nucleic Acids Research
Year: 2013
Volume: 41
Issue: 8
Pages: 4433-4446
Print publication date: 21/02/2013
Date deposited: 11/07/2013
ISSN (print): 0305-1048
ISSN (electronic): 1362-4962
Publisher: Oxford University Press
URL: http://dx.doi.org/10.1093/nar/gkt106
DOI: 10.1093/nar/gkt106
PubMed id: 23435229
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