Silencing of androgen-regulated genes using a fusion of AR with the PLZF transcriptional repressor.
The androgen receptor (AR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays a key role in the development and progression of prostate cancer. Current therapies include the use of antiandrogens aimed at inhibiting the transcriptional activation of AR-regulated genes by AR. Here, we explore a strategy aimed at obtaining silencing of AR-regulated genes, based on the properties of the transcriptional repressor promyelocytic leukamia zinc-finger protein (PLZF). In order to do this, we have made a fusion protein between PLZF and AR, named PLZF-AR, and show that PLZF-AR is able to bring about silencing of genomically encoded AR-regulated genes and inhibit the androgen-regulated growth of LNCaP prostate cancer cells. Together, our results show that this strategy is able to bring about potent repression of AR-regulated responses and, therefore, could be of value in the development of new therapies for prostate cancer.
Pike
Joanna
J
Department of Cancer Medicine, Imperial College London, Du Cane Road, W12 0NN, UK.
Holmes
David
D
Kamalati
Tahereh
T
Davies
Derek
D
Tolhurst
Robert
R
Mazhar
Danish
D
Fishpool
Sam
S
al-Jehani
Rajai
R
Waxman
Jonathan
J
Zelent
Arthur
A
Lemoine
Nicholas R
NR
Ali
Simak
S
Buluwela
Laki
L
D000728:Androgens / Q000502:physiology*; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D017930:Genes, Reporter; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011944:Receptors, Androgen / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*
D000728:Androgens; D017931:DNA Primers; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C092037:ZBTB16 protein, human