Identification of transcription factors associated with castration-resistance: is the serum responsive factor a potential therapeutic target?
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.


CONCLUSIONS
SRF is a key TF by which resistant cells survive with depleted levels of androgens representing a target for therapeutic manipulation.
UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland. maria.prencipe@ucd.ie
Maria
M
Prencipe
Stephen F
SF
Madden
Amanda
A
O'Neill
Gillian
G
O'Hurley
Aedin
A
Culhane
Darran
D
O'Connor
Helmut
H
Klocker
Elaine W
EW
Kay
William M
WM
Gallagher
William R
WR
Watson
D000728:Androgens / Q000494:pharmacology*; D015153:Blotting, Western; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D034741:RNA, Small Interfering; D026362:Serum Response Factor / Q000378:metabolism*
D000728:Androgens; D034741:RNA, Small Interfering; D026362:Serum Response Factor