title: Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate-resistant prostate cancer.
abstract: Castrate-resistant prostate cancer (CRPC) progression is a complex process by which prostate cells acquire the ability to survive and proliferate in the absence or under very low levels of androgens. Most CRPC tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes owing to reactivation of AR. Protein tyrosine kinases have been implicated in supporting AR activation under castrate conditions. Here we report that Lyn tyrosine kinase expression is upregulated in CRPC human specimens compared with hormone naive or normal tissue. Lyn overexpression enhanced AR transcriptional activity both in vitro and in vivo and accelerated CRPC. Reciprocally, specific targeting of Lyn resulted in a decrease of AR transcriptional activity in vitro and in vivo and prolonged time to castration. Mechanistically, we found that targeting Lyn kinase induces AR dissociation from the molecular chaperone Hsp90, leading to its ubiquitination and proteasomal degradation. This work indicates a novel mechanism of regulation of AR stability and transcriptional activity by Lyn and justifies further investigation of the Lyn tyrosine kinase as a therapeutic target for the treatment of CRPC.Oncogenesis (2014) 3, e115; doi:10.1038/oncsis.2014.30; published online 18 August 2014.
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Zardan
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Nip
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Thaper
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Toren
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Vahid
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Beraldi
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Fazli
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Gust
authors.affiliation: 1] The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada [2] Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: M E
authors.initials: ME
authors.lastname: Cox
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: J L
authors.initials: JL
authors.lastname: Bishop
authors.affiliation: 1] The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada [2] Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Zoubeidi