title: Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover.
abstract: The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 [nuclear receptor coactivator (NCOA)2], and SRC-3 [amplified in breast cancer 1 (AIB1)/NCOA3] are key pleiotropic "master regulators" of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play critical roles in androgen receptor transcriptional activity, cell proliferation, and resistance to androgen deprivation therapy. We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. Interestingly, somatic heterozygous missense mutations in the SPOP substrate-binding cleft recently were identified in up to 15% of human PCs (making SPOP the gene most commonly affected by nonsynonymous point mutations in PC), but their contribution to PC pathophysiology remains unknown. We now report that PC-associated SPOP mutants cannot interact with SRC-3 protein or promote its ubiquitination and degradation. Our data suggest that wild-type SPOP plays a critical tumor suppressor role in PC cells, promoting the turnover of SRC-3 protein and suppressing androgen receptor transcriptional activity. This tumor suppressor effect is abrogated by the PC-associated SPOP mutations. These studies provide a possible explanation for the role of SPOP mutations in PC, and highlight the potential of SRC-3 as a therapeutic target in PC.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Geng
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Limei
authors.initials: L
authors.lastname: Xu
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Barbieri
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Eedunuri
authors.forename: Sue Anne
authors.initials: SA
authors.lastname: Chew
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Richard
authors.initials: R
authors.lastname: Bond
authors.forename: John
authors.initials: J
authors.lastname: Shou
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Mirjam
authors.initials: M
authors.lastname: Blattner
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000704:Analysis of Variance; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016086:Lentivirus; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D009687:Nuclear Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; C509761:SPOP protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3; C022616:thiazolyl blue
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