title: Silencing of androgen-regulated genes using a fusion of AR with the PLZF transcriptional repressor.
abstract: 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.
authors.affiliation: Department of Cancer Medicine, Imperial College London, Du Cane Road, W12 0NN, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pike
authors.forename: David
authors.initials: D
authors.lastname: Holmes
authors.forename: Tahereh
authors.initials: T
authors.lastname: Kamalati
authors.forename: Derek
authors.initials: D
authors.lastname: Davies
authors.forename: Robert
authors.initials: R
authors.lastname: Tolhurst
authors.forename: Danish
authors.initials: D
authors.lastname: Mazhar
authors.forename: Sam
authors.initials: S
authors.lastname: Fishpool
authors.forename: Rajai
authors.initials: R
authors.lastname: al-Jehani
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Arthur
authors.initials: A
authors.lastname: Zelent
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
authors.forename: Laki
authors.initials: L
authors.lastname: Buluwela
mesh_terms: 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*
chemical_list: 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