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E6AP通过降低p27表达促进前列腺癌。

E6AP promotes prostate cancer by reducing p27 expression.

作者信息

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

机构信息

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

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

出版信息

Oncotarget. 2017 Jun 27;8(26):42939-42948. doi: 10.18632/oncotarget.17224.

DOI:10.18632/oncotarget.17224
PMID:28477016
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5522117/
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.

摘要

前列腺癌（PC）是男性中最常见的癌症。E3 连接酶 E6 相关蛋白（E6AP）水平升高先前与前列腺癌有关，这与一部分前列腺癌患者中蛋白质表达增加相一致。在癌症中，异常的 E3 连接酶活性驱动肿瘤抑制蛋白的蛋白酶体降解。因此，E3 连接酶抑制剂是恢复肿瘤抑制的合理疗法。E6AP 在前列腺癌中靶向的相关肿瘤抑制因子尚未完全确定。在本研究中，我们表明关键细胞周期调节因子 p27 是前列腺癌中 E6AP 的一个靶点。E6AP 的下调增加了 p27 的表达并增强了其在前列腺癌中的核积累。我们证明 E6AP 通过以 E2F1 依赖的方式抑制 p27 的转录来调节其表达。同时敲低 E6AP 和 p27 可部分恢复前列腺癌细胞的生长，支持 p27 对 E6AP 对前列腺肿瘤发生总体影响的作用。总体而言，我们揭示了 E6AP - p27 轴是前列腺癌的一个新的促进因子，通过恢复肿瘤抑制作用暴露了一个有吸引力的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/9d21f6da2a12/oncotarget-08-42939-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/ba278aa75678/oncotarget-08-42939-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/9f77a655786b/oncotarget-08-42939-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/da7063021350/oncotarget-08-42939-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/8fd13bf153c0/oncotarget-08-42939-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/dbab821da949/oncotarget-08-42939-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/9d21f6da2a12/oncotarget-08-42939-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/ba278aa75678/oncotarget-08-42939-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/9f77a655786b/oncotarget-08-42939-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/da7063021350/oncotarget-08-42939-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/8fd13bf153c0/oncotarget-08-42939-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/dbab821da949/oncotarget-08-42939-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ffdf/5522117/9d21f6da2a12/oncotarget-08-42939-g006.jpg

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