Regulation of tumor suppressor EAF2 polyubiquitination by ELL1 and SIAH2 in prostate cancer cells
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Xinpei Yu1,5,8,9, Junkui Ai1, Liquan Cai1, Yifeng Jing1,6, Dan Wang1, Jun Dong1, Laura E. Pascal1, Jian Zhang7, Rongcheng Luo8, Zhou Wang1,2,3,4
1Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, USA
2Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, USA
3Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, USA
4University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, USA
5Department of Geriatrics, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China
6Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
7Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, China
8Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, China
9Guangdong Provincial Key Laboratory of Geriatric Infection and Organ Function Support and Guangzhou Key Laboratory of Geriatric Infection and Organ Function Support, Guangzhou, China
Zhou Wang, email: firstname.lastname@example.org
Rongcheng Luo, email: email@example.com
Keywords: prostate cancer, EAF2, ELL, SIAH2, ubiquitination
Received: October 06, 2015 Accepted: March 16, 2016 Published: April 05, 2016
RNA Polymerase II Elongation Factor (ELL)-associated factor 2 (EAF2) is a tumor suppressor frequently down-regulated in human prostate cancer. We previously reported that its binding partner ELL1 can enhance EAF2 protein stability and activity. Here we show that EAF2 can be polyubiquitinated and its degradation blocked by proteasome inhibitor. Co-immunoprecipitation detected EAF2 binding to SIAH2, an E3 ligase, and SIAH2 overexpression enhanced polyubiquitination of EAF2. Co-transfection of EAF2 binding partner ELL1 blocked EAF2 ubiquitination, providing a mechanism for EAF2 stabilization. Finally, EAF2K81R mutant, which exhibits reduced polyubiquitination and increased stability, was more potent than wild-type EAF2 in apoptosis induction. These findings suggest that SIAH2 is an E3 ligase for EAF2 polyubiquitination and ELL1 can enhance EAF2 level and function by blocking its polyubiquitination.
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