Oncotarget

Research Papers:

E6AP promotes prostate cancer by reducing p27 expression

Dinesh Raghu, Piotr Jan Paul, Twishi Gulati, Siddhartha Deb, Christine Khoo, Andrea Russo, Enzo Gallo, Giovanni Blandino, Ai-Leen Chan, Elena Takano, Shahneen K. Sandhu, Stephen B. Fox, Scott Williams, Sue Haupt, Cristina Gamell and Ygal Haupt _

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Oncotarget. 2017; 8:42939-42948. https://doi.org/10.18632/oncotarget.17224

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Abstract

Dinesh Raghu1,2, Piotr Jan Paul1,2, Twishi Gulati1,2, Siddhartha Deb3, Christine Khoo4, Andrea Russo5, Enzo Gallo5, Giovanni Blandino6, Ai-Leen Chan2,11, Elena Takano4, Shahneen K. Sandhu7, Stephen B. Fox4, Scott Williams8, Sue Haupt1,2, Cristina Gamell1,2,* and Ygal Haupt1,2,9,10,*

1The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

2Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

3Anatpath Services Pty Ltd, Gardenvale, Victoria, Australia

4Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

5Department of Surgical Pathology, Regina Elena Cancer Institute, Rome, Italy

6Oncogenomic and Epigenetic Unit, Italian National Cancer Institute, Rome, Italy

7Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

8Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

9Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia

10Department of Pathology, The University of Melbourne, Melbourne, Victoria, Australia

11Current address: Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia

*Both authors have shared co-senior authorship

Correspondence to:

Ygal Haupt, email: [email protected]

Keywords: prostate cancer, E6AP, p27, E2F1, tumor suppression

Received: February 07, 2017     Accepted: March 16, 2017     Published: April 19, 2017

ABSTRACT

Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC. Down regulation of E6AP increases p27 expression and enhances its nuclear accumulation in PC. We demonstrate that E6AP regulates p27 expression by inhibiting its transcription in an E2F1-dependent manner. Concomitant knockdown of E6AP and p27 partially restores PC cell growth, supporting the contribution of p27 to the overall effect of E6AP on prostate tumorigenesis. Overall, we unravelled the E6AP-p27 axis as a new promoter of PC, exposing an attractive target for therapy through the restoration of tumor suppression.


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