title: Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer.
abstract: Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Geng
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Kimal
authors.initials: K
authors.lastname: Rajapakshe
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Shrijal S
authors.initials: SS
authors.lastname: Shah
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: John
authors.initials: J
authors.lastname: Shou
authors.affiliation: Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Eedunuri
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Christopher
authors.initials: C
authors.lastname: Foley
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Mahitha
authors.initials: M
authors.lastname: Rajendran
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Sue Anne
authors.initials: SA
authors.lastname: Chew
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard
authors.initials: R
authors.lastname: Bond
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. mitsiade@bcm.edu coarfa@bcm.edu.
authors.forename: Cristian
authors.initials: C
authors.lastname: Coarfa
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas. Center for Drug Discovery, Baylor College of Medicine, Houston, Texas. mitsiade@bcm.edu coarfa@bcm.edu.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsiades
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000503:physiopathology*; D000728:Androgens / Q000502:physiology; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D056921:Nuclear Receptor Coactivator 3 / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000503:physiopathology*; D011944:Receptors, Androgen / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000728:Androgens; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D012097:Repressor Proteins; C509761:SPOP protein, human; C538866:NCOA3 protein, human; D056921:Nuclear Receptor Coactivator 3