PMID- 27641331
OWN - NLM
STAT- MEDLINE
DCOM- 20170906
LR  - 20181113
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 48
DP  - 2016 Dec 1
TI  - Restoration of tumor suppression in prostate cancer by targeting the E3 ligase 
      E6AP.
PG  - 6235-6245
LID - 10.1038/onc.2016.159 [doi]
AB  - 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.
FAU - Paul, P J
AU  - Paul PJ
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Melbourne, Victoria, Australia.
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Raghu, D
AU  - Raghu D
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Melbourne, Victoria, Australia.
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Chan, A-L
AU  - Chan AL
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Gulati, T
AU  - Gulati T
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Melbourne, Victoria, Australia.
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Lambeth, L
AU  - Lambeth L
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Takano, E
AU  - Takano E
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Herold, M J
AU  - Herold MJ
AD  - Molecular Genetics of Cancer, The Walter and Eliza Hall Institute, Parkville, 
      Victoria, Australia.
AD  - Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 
      Australia.
FAU - Hagekyriakou, J
AU  - Hagekyriakou J
AD  - Department of Physical Sciences, Peter MacCallum Cancer Centre, Melbourne, 
      Victoria, Australia.
FAU - Vessella, R L
AU  - Vessella RL
AD  - Department of Urology, University of Washington, Seattle, WA, USA.
FAU - Fedele, C
AU  - Fedele C
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
AD  - Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
AD  - Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
FAU - Shackleton, M
AU  - Shackleton M
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
AD  - Cancer Development and Treatment Laboratory, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
AD  - Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
FAU - Williams, E D
AU  - Williams ED
AUID- ORCID: 0000-0002-3364-6655
AD  - Australian Prostate Cancer Research Centre-Queensland University of Technology, 
      Brisbane, Queensland, Australia.
FAU - Fox, S
AU  - Fox S
AD  - Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Williams, S
AU  - Williams S
AD  - Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
FAU - Haupt, S
AU  - Haupt S
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Gamell, C
AU  - Gamell C
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
FAU - Haupt, Y
AU  - Haupt Y
AD  - The Sir Peter MacCallum Department of Oncology, The University of Melbourne, 
      Melbourne, Victoria, Australia.
AD  - Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 
      Australia.
AD  - Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, 
      Melbourne, Victoria, Australia.
AD  - Department of Biochemistry and Molecular Biology, Monash University, Melbourne, 
      Victoria, Australia.
AD  - Department of Pathology, The University of Melbourne, Melbourne, Victoria, 
      Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160919
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Promyelocytic Leukemia Protein)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.3.2.26 (UBE3A protein, human)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Animals
MH  - Cell Cycle/genetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cell Survival/genetics
MH  - Cellular Senescence/genetics
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Gene Expression
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Knockdown Techniques
MH  - Heterografts
MH  - Humans
MH  - Male
MH  - Mice
MH  - Prognosis
MH  - Promyelocytic Leukemia Protein/genetics/metabolism
MH  - Prostatic Neoplasms/*genetics/mortality/*pathology
MH  - RNA, Small Interfering/genetics
MH  - Stress, Physiological
MH  - Tumor Burden
MH  - Ubiquitin-Protein Ligases/*genetics
EDAT- 2016/09/20 06:00
MHDA- 2017/09/07 06:00
CRDT- 2016/09/20 06:00
PHST- 2015/08/27 00:00 [received]
PHST- 2016/03/22 00:00 [revised]
PHST- 2016/03/31 00:00 [accepted]
PHST- 2016/09/20 06:00 [pubmed]
PHST- 2017/09/07 06:00 [medline]
PHST- 2016/09/20 06:00 [entrez]
AID - onc2016159 [pii]
AID - 10.1038/onc.2016.159 [doi]
PST - ppublish
SO  - Oncogene. 2016 Dec 1;35(48):6235-6245. doi: 10.1038/onc.2016.159. Epub 2016 Sep 
      19.