title: Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6.
abstract: In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation, and immune signaling pathways and maintained gene expression patterns normally decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer. Cancer Res; 77(3); 753-65. ©2016 AACR.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Atish D
authors.initials: AD
authors.lastname: Choudhury
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schinzel
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Maura B
authors.initials: MB
authors.lastname: Cotter
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Rosina T
authors.initials: RT
authors.lastname: Lis
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Katherine
authors.initials: K
authors.lastname: Labella
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ying Jie
authors.initials: YJ
authors.lastname: Lock
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Francesca
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Isil
authors.initials: I
authors.lastname: Guney
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bowden
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yvonne Y
authors.initials: YY
authors.lastname: Li
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Jinal
authors.initials: J
authors.lastname: Patel
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Emily
authors.initials: E
authors.lastname: Hartman
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Jaffe
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Kantoff
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. william_hahn@dfci.harvard.edu.|Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D064593:Heterografts; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D000072379:NIMA-Related Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology*; D059467:Transcriptome
chemical_list: C408469:FOXJ2 protein, human; D051858:Forkhead Transcription Factors; C459456:NEK6 protein, human; D000072379:NIMA-Related Kinases