title: Skp2 deficiency restricts the progression and stem cell features of castration-resistant prostate cancer by destabilizing Twist.
abstract: Castration-resistant prostate cancer (CRPC) remains a major clinical challenge because of the lack of effective targeted therapy for its treatment. The mechanism underlying how CRPC gains resistance toward hormone depletion and other forms of chemotherapy is poorly understood. Research on understanding the factors that drive these processes is desperately needed to generate new therapies to cure the disease. Here, we discovered a fundamental role of S-phase protein kinase 2 (Skp2) in the formation and progression of CRPC. In transgenic adenocarcinoma mouse prostate model, Skp2 depletion leads to a profound repression of prostate tumor growth and distal metastasis and substantially prolonged overall survival. We revealed that Skp2 regulates CRPC through Twist-mediated oncogenic functions including epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) acquisitions. Mechanistically, Skp2 interacted with Twist and promoted the non-degradative ubiquitination of Twist. Consequently, Skp2 stabilized Twist protein expression by preventing proteasomal degradation of Twist by β-TrCP. We found that Twist overexpression augments CSC self-renewal and population and that Skp2 inhibition reverts Twist's effects on CSC regulation. Furthermore, genetically depleting or pharmacologically inactivating Skp2 synergistically re-sensitized CRPC cells toward chemotherapies such as paclitaxel or doxorubicin. Together, this study uncovering Skp2-mediated Twist stabilization and oncogenic functions in CRPC offers new knowledge on how CRPC progresses and acquires chemoresistance during tumor progression. It provides proof of principle that Skp2 targeting is a promising approach to combat metastatic CRPC by targeting Twist and CSCs.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Ruan
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pathology, Chi-Mei Foundational Medical Center, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
authors.forename: C-F
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pathology, Stony Brook University, Stony Brook, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.|Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: H-K
authors.initials: HK
authors.lastname: Lin
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY, USA.|Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA.|Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D044786:S-Phase Kinase-Associated Proteins; D051879:Twist-Related Protein 1