Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Gulati, Twishi × Author: Sandhu, Shahneen × End date: 2019 × Start date: 2017 ×

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    E6AP promotes prostate cancer by reducing p27 expression
    Raghu, D ; Paul, PJ ; Gulati, T ; Deb, S ; Khoo, C ; Russo, A ; Gallo, E ; Blandino, G ; Chan, A-L ; Takano, E ; Sandhu, SK ; Fox, SB ; Williams, S ; Haupt, S ; Gamell, C ; Haupt, Y (IMPACT JOURNALS LLC, 2017-06-27)
    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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    E6AP Promotes a Metastatic Phenotype in Prostate Cancer
    Gamell, C ; Bandilovska, I ; Gulati, T ; Kogan, A ; Lim, SC ; Kovacevic, Z ; Takano, EA ; Timpone, C ; Agupitan, AD ; Litchfield, C ; Blandino, G ; Horvath, LG ; Fox, SB ; Williams, SG ; Russo, A ; Gallo, E ; Paul, PJ ; Mitchell, C ; Sandhu, S ; Keam, SP ; Haupt, S ; Richardson, DR ; Haupt, Y (CELL PRESS, 2019-12-20)
    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.