title: Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer.
abstract: Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, patients undergoing androgen-deprivation therapy (ADT) for disseminated PCa eventually develop castration-resistant PCa (CRPC). Results of previous studies indicated that AR, a transcription factor, occupies distinct genomic loci in CRPC compared with hormone-naïve PCa; however, the cause of this distinction was unknown. The E3 ubiquitin ligase Nrdp1 is a model AR target modulated by androgens in hormone-naïve PCa but not in CRPC. Using Nrdp1, we investigated how AR switches transcription programs during CRPC progression. The proximal Nrdp1 promoter contains an androgen response element (ARE); we demonstrated AR binding to this ARE in androgen-sensitive PCa. Analysis of hormone-naive human prostatectomy specimens revealed correlation between Nrdp1 and AR expression, supporting AR regulation of NRDP1 levels in androgen-sensitive tissue. However, despite sustained AR levels, AR binding to the Nrdp1 promoter and Nrdp1 expression were suppressed in CRPC. Elucidation of the suppression mechanism demonstrated correlation of NRDP1 levels with nuclear localization of the scaffolding protein filamin A (FLNA) which, as we previously showed, is itself repressed following ADT in many CRPC tumors. Restoration of nuclear FLNA in CRPC stimulated AR binding to Nrdp1 ARE, increased its transcription, and augmented NRDP1 protein expression and responsiveness to ADT, indicating that nuclear FLNA controls AR-mediated androgen-sensitive Nrdp1 transcription. Expression of other AR-regulated genes lost in CRPC was also re-established by nuclear FLNA. Thus, our results indicate that nuclear FLNA promotes androgen-dependent AR-regulated transcription in PCa, while loss of nuclear FLNA in CRPC alters the AR-regulated transcription program.
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Rosalinda M
authors.initials: RM
authors.lastname: Savoy
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Chen
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Salma
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Frank U
authors.initials: FU
authors.lastname: Melgoza
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Blythe
authors.initials: B
authors.lastname: Durbin-Johnson
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Christiana
authors.initials: C
authors.lastname: Drake
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Maitreyee K
authors.initials: MK
authors.lastname: Jathal
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Swagata
authors.initials: S
authors.lastname: Bose
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Steele
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Mooso
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Leandro S
authors.initials: LS
authors.lastname: D'Abronzo
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Fry
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Kermit L
authors.initials: KL
authors.lastname: Carraway
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mudryj
authors.affiliation: VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA VA Northern California Health Care SystemMather, California, USADepartment of UrologySchool of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Sacramento, California 95817, USADivision of BiostatisticsDepartment of Public Health Sciences, University of California Davis, Davis, California, USADepartment of StatisticsUniversity of California Davis, Davis, California, USADepartment of Biochemistry and Molecular MedicineUniversity of California Davis, Sacramento, California, USADepartment of Medical Microbiology and ImmunologyUniversity of California Davis, Davis, California, USA paramita.ghosh@ucdmc.ucdavis.edu.
authors.forename: Paramita M
authors.initials: PM
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D064448:Filamins / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C410798:AR protein, human; C578663:FLNA protein, human; D064448:Filamins; D011944:Receptors, Androgen; C452580:RNF41 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ABP280/filamin A; AR/androgen receptor; FLRF/RNF41/Nrdp1; HER3/ErbB3; castration-resistant prostate cancer