title: The HIF/PHF8/AR axis promotes prostate cancer progression.
abstract: Recent studies provide strong evidence that the androgen receptor (AR) signaling pathway remains active in castration-resistant prostate cancer (CRPC). However, the underlying mechanisms are not well understood. In this study, we demonstrate that plant homeo domain finger protein 8 (PHF8 )interacts with and functions as an essential histone demethylase activity-dependent AR coactivator. Furthermore, we demonstrate that the expression of PHF8 is induced by hypoxia in various prostate cancer cell lines. Knockdown of either hypoxia-inducible factor HIF2α or HIF1α almost completely abolished hypoxia-induced PHF8 expression. Importantly, we observed that PHF8 is highly expressed in clinical androgen deprived prostate cancer samples and expression of PHF8 correlates with increased levels of HIF1α and HIF2α. Moreover, elevated PHF8 is associated with higher grade prostate cancers and unfavorable outcomes. Our findings support a working model in which hypoxia in castrated prostate cancer activates HIF transcription factors which then induces PHF8 expression. The elevated PHF8 in turn promotes the AR signaling pathway and prostate cancer progression. Therefore, the HIF/PHF8/AR axis could serve as a potential biomarker for CRPC and is also a promising therapeutic target in combating CRPC.
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: D
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Ultrasound, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: W
authors.initials: W
authors.lastname: Lan
authors.affiliation: Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Sbarro Institute for Cancer Research, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Mu
authors.affiliation: Department of Pathology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: C
authors.initials: C
authors.lastname: Mao
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Wong
authors.affiliation: Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: J
authors.initials: J
authors.lastname: Jiang