title: The cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cells.
abstract: OBJECTIVE
  Spliced variant forms of androgen receptor were recently identified in castration resistant prostate cancer cell lines and clinical samples. We identified the cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cell lines and determined the clinical significance of androgen receptor splice variant regulated genes.
  
  
  METHODS
  The castration resistant prostate cancer cell line 22Rv1, which expresses full-length androgen receptor and androgen receptor splice variants endogenously, was used as the research model. We established 22Rv1-ARFL(-)/ARV(+) and 22Rv1-ARFL(-)/ARV(-) through RNA interference. Chromatin immunoprecipitation coupled with next generation sequencing and microarray techniques were used to identify the cistrome and gene expression profiles of androgen receptor splice variants in the absence of androgen.
  
  
  RESULTS
  Androgen receptor splice variant binding sites were identified in 22Rv1-ARFL(-)/ARV(+). A gene set was regulated uniquely by androgen receptor splice variants but not by full-length androgen receptor in the absence of androgen. Integrated analysis revealed that some genes were directly modulated by androgen receptor splice variants. Unsupervised clustering analysis showed that the androgen receptor splice variant gene signature differentiated benign from malignant prostate tissue as well as localized prostate cancer from metastatic castration resistant prostate cancer specimens. Some genes that were modulated uniquely by androgen receptor splice variants also correlated with histological grade and biochemical failure.
  
  
  CONCLUSIONS
  Androgen receptor splice variants can bind to DNA independent of full-length androgen receptor in the absence of androgen and modulate a unique set of genes that is not regulated by full-length androgen receptor. The androgen receptor splice variant gene signature correlates with disease progression. It distinguishes primary cancer from castration resistant prostate cancer specimens and benign from malignant prostate specimens.
authors.affiliation: Department of Urology, First Hospital of Jilin University, Changchun, People's Republic of China; Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ji
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lonergan
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lucas P
authors.initials: LP
authors.lastname: Nacusi
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Liguo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Schmidt
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Travis
authors.initials: T
authors.lastname: Van der Steen
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Boorjian
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Farhad
authors.initials: F
authors.lastname: Kosari
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: George G
authors.initials: GG
authors.lastname: Klee
authors.affiliation: Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Balk
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Urology, First Hospital of Jilin University, Changchun, People's Republic of China. Electronic address: chunxi_wang@126.com.
authors.forename: Chunxi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. Electronic address: tindall@mayo.edu.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tindall
mesh_terms: D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D020033:Protein Isoforms; D011944:Receptors, Androgen / Q000235:genetics*; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D020033:Protein Isoforms; D011944:Receptors, Androgen
keywords: alternative splicing; androgen; castration-resistant; disease progression; prostatic neoplasms; receptors; transcriptome