Sir Peter MacCallum Department of Oncology - Research Publications

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    MDM4 is a rational target for treating breast cancers with mutant p53
    Miranda, PJ ; Buckley, D ; Raghu, D ; Pang, J-MB ; Takano, EA ; Vijayakumaran, R ; Teunisse, AFAS ; Posner, A ; Procter, T ; Herold, MJ ; Gamell, C ; Marine, J-C ; Fox, SB ; Jochemsen, A ; Haupt, S ; Haupt, Y (WILEY, 2017-04)
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    p53 calls upon CIA (Calcium Induced Apoptosis) to counter stress
    Haupt, S ; Raghu, D ; Haupt, Y (FRONTIERS MEDIA SA, 2015-03-10)
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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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    Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP
    Paul, PJ ; Raghu, D ; Chan, A-L ; Gulati, T ; Lambeth, L ; Takano, E ; Herold, MJ ; Hagekyriakou, J ; Vessella, RL ; Fedele, C ; Shackleton, M ; Williams, ED ; Fox, S ; Williams, S ; Haupt, S ; Gamell, C ; Haupt, Y (NATURE PUBLISHING GROUP, 2016-12-01)
    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.