E6AP Promotes a Metastatic Phenotype in Prostate Cancer

Cristina Gamell; Ivona Bandilovska; Twishi Gulati; Arielle Kogan; Syer Choon Lim; Zaklina Kovacevic; Elena A Takano; Clelia Timpone; Arjelle D Agupitan; Cassandra Litchfield; Giovanni Blandino; Lisa G Horvath; Stephen B Fox; Scott G Williams; Andrea Russo; Enzo Gallo; Piotr J Paul; Catherine Mitchell; Shahneen Sandhu; Simon P Keam; Sue Haupt; Des R Richardson; Ygal Haupt

doi:10.1016/j.isci.2019.10.065

E6AP Promotes a Metastatic Phenotype in Prostate Cancer

iScience. 2019 Dec 20:22:1-15. doi: 10.1016/j.isci.2019.10.065. Epub 2019 Nov 2.

Authors

Cristina Gamell¹, Ivona Bandilovska¹, Twishi Gulati², Arielle Kogan¹, Syer Choon Lim³, Zaklina Kovacevic³, Elena A Takano⁴, Clelia Timpone¹, Arjelle D Agupitan¹, Cassandra Litchfield¹, Giovanni Blandino⁵, Lisa G Horvath⁶, Stephen B Fox⁷, Scott G Williams⁸, Andrea Russo⁵, Enzo Gallo⁵, Piotr J Paul¹, Catherine Mitchell⁴, Shahneen Sandhu², Simon P Keam⁹, Sue Haupt⁹, Des R Richardson¹⁰, Ygal Haupt¹¹

Affiliations

¹ Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia.
² Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
³ Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia.
⁴ Department of Pathology, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.
⁵ IRCCS Regina Elena National Cancer Institute, Rome, Italy.
⁶ The Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia; Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
⁷ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.
⁸ Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
⁹ Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
¹⁰ Department of Pathology and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
¹¹ Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne 3000, Australia; Department of Clinical Pathology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, Australia. Electronic address: [email protected].

Abstract

Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.

Keywords: Biological Sciences; Cancer; Cell Biology.