title: Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis.
abstract: SLUG represses E-cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19(Arf) (p14(ARF) in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19(Arf) reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14(ARF) stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14(ARF) are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner.
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208, USA.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208, USA.
authors.forename: Shenji
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208, USA.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Human Tissue and Pathology Core Facility, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Kieosha D
authors.initials: KD
authors.lastname: Williams
authors.affiliation: Department of Pathology, Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Awadh A
authors.initials: AA
authors.lastname: Binhazim
authors.affiliation: Department of Surgery, Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.affiliation: Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 Dr. D. B. Todd Jr. Blvd, Nashville, TN 37208, USA. Electronic address: zchen@mmc.edu.
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D008297:Male; D051379:Mice; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D025842:SUMO-1 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D015820:Cadherins; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C000604407:SNAI1 protein, human; D025842:SUMO-1 Protein; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
keywords: Mouse model; Prostate cancer; SLUG; SUMO1