TY - JOUR
T1 - Identification of transcription factors associated with castration-resistance
T2 - Is the serum responsive factor a potential therapeutic target?
AU - Prencipe, Maria
AU - Madden, Stephen F.
AU - O'Neill, Amanda
AU - O'Hurley, Gillian
AU - Culhane, Aedin
AU - O'Connor, Darran
AU - Klocker, Helmut
AU - Kay, Elaine W.
AU - Gallagher, William M.
AU - Watson, William R.
N1 - Copyright © 2013 Wiley Periodicals, Inc.
PY - 2013/5
Y1 - 2013/5
N2 - BACKGROUND Advanced prostate cancer is treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse to develop castration-resistant disease for which there are no effective treatments. We have previously shown that manipulating individual proteins has only minor alterations on the resistant phenotype so we hypothesize that targeting the central transcription factors (TFs) would represent a better therapeutic approach. METHODS We have undertaken a transcriptomic analysis of gene expression differences between the androgen-dependent LNCaP parental cells and its castration-resistant Abl and Hof sublines, revealing 1,660 genes associated with castration-resistance. Using effective bioinformatic techniques, these transcriptomic data were integrated with TF binding sites resulting in a list of TFs associated with the differential gene expression observed. RESULTS Following validation of the gene-chip results, the serum response factor (SRF) was chosen for clinical validation and functional analysis due to its recent association with prostate cancer progression. SRF immunoreactivity in prostate tumor samples was shown for the first time to be associated with castration-resistance. SRF inhibition by siRNA and the small molecule inhibitor CCG-1423 resulted in decreased proliferation. CONCLUSION SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation. Prostate 73: 743-753, 2013. © 2013 Wiley Periodicals, Inc.
AB - BACKGROUND Advanced prostate cancer is treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse to develop castration-resistant disease for which there are no effective treatments. We have previously shown that manipulating individual proteins has only minor alterations on the resistant phenotype so we hypothesize that targeting the central transcription factors (TFs) would represent a better therapeutic approach. METHODS We have undertaken a transcriptomic analysis of gene expression differences between the androgen-dependent LNCaP parental cells and its castration-resistant Abl and Hof sublines, revealing 1,660 genes associated with castration-resistance. Using effective bioinformatic techniques, these transcriptomic data were integrated with TF binding sites resulting in a list of TFs associated with the differential gene expression observed. RESULTS Following validation of the gene-chip results, the serum response factor (SRF) was chosen for clinical validation and functional analysis due to its recent association with prostate cancer progression. SRF immunoreactivity in prostate tumor samples was shown for the first time to be associated with castration-resistance. SRF inhibition by siRNA and the small molecule inhibitor CCG-1423 resulted in decreased proliferation. CONCLUSION SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation. Prostate 73: 743-753, 2013. © 2013 Wiley Periodicals, Inc.
KW - advanced prostate cancer
KW - serum response factor (SRF)
KW - transcription-factors prediction analysis
UR - http://www.scopus.com/inward/record.url?scp=84876287828&partnerID=8YFLogxK
U2 - 10.1002/pros.22618
DO - 10.1002/pros.22618
M3 - Article
C2 - 23359479
AN - SCOPUS:84876287828
SN - 0270-4137
VL - 73
SP - 743
EP - 753
JO - Prostate
JF - Prostate
IS - 7
ER -