title: Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP.
abstract: Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.
authors.affiliation: The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Paul
authors.affiliation: The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Raghu
authors.affiliation: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: A-L
authors.initials: AL
authors.lastname: Chan
authors.affiliation: The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Gulati
authors.affiliation: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Lambeth
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Takano
authors.affiliation: Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Herold
authors.affiliation: Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Hagekyriakou
authors.affiliation: Department of Urology, University of Washington, Seattle, WA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Fedele
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: E D
authors.identifier: 0000-0002-3364-6655
authors.initials: ED
authors.lastname: Williams
authors.affiliation: Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Fox
authors.affiliation: Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Williams
authors.affiliation: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Haupt
authors.affiliation: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Gamell
authors.affiliation: The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.|Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.|Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.|Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Y
authors.initials: Y
authors.lastname: Haupt
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D011379:Prognosis; D000071156:Promyelocytic Leukemia Protein / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D013312:Stress, Physiological; D047368:Tumor Burden; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases