title: SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination.
abstract: Aberrant elevation of JARID1B and histone H3 lysine 4 trimethylation (H3K4me3) is frequently observed in many diseases including prostate cancer (PCa), yet the mechanisms on the regulation of JARID1B and H3K4me3 through epigenetic alterations still remain poorly understood. Here we report that Skp2 modulates JARID1B and H3K4me3 levels in vitro in cultured cells and in vivo in mouse models. We demonstrated that Skp2 inactivation decreased H3K4me3 levels, along with a reduction of cell growth, cell migration and malignant transformation of Pten/Trp53 double null MEFs, and further restrained prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, Skp2 decreased the K63-linked ubiquitination of JARID1B by E3 ubiquitin ligase TRAF6, thus decreasing JARID1B demethylase activity and in turn increasing H3K4me3. In agreement, Skp2 deficiency resulted in an increase of JARID1B ubiquitination and in turn a reduction of H3K4me3, and induced senescence through JARID1B accumulation in nucleoli of PCa cells and prostate tumors of mice. Furthermore, we showed that the elevations of Skp2 and H3K4me3 contributed to castration-resistant prostate cancer (CRPC) in mice, and were positively correlated in human PCa specimens. Taken together, our findings reveal a novel network of SKP2-JARID1B, and targeting SKP2 and JARID1B may be a potential strategy for PCa control.
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Shenji
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Adhiambo
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Billy R
authors.initials: BR
authors.lastname: Ballard
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Department of Urologic Surgery, Vanderbilt University School of Medicine, TN 37232, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA.
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D044786:S-Phase Kinase-Associated Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; C485614:Kdm5b protein, mouse