Research Papers:

SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination

Wenfu Lu _, Shenji Liu, Bo Li, Yingqiu Xie, Christine Adhiambo, Qing Yang, Billy R. Ballard, Keiichi I. Nakayama, Robert J. Matusik and Zhenbang Chen

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Oncotarget. 2015; 6:771-788. https://doi.org/10.18632/oncotarget.2718

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Wenfu Lu1, Shenji Liu1, Bo Li1, Yingqiu Xie1, Christine Adhiambo1, Qing Yang1, Billy R. Ballard2, Keiichi I. Nakayama3, Robert J. Matusik4, Zhenbang Chen1

1Department of Biochemistry and Cancer Biology, Meharry Medical College, TN 37208, USA

2Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, TN 37208, USA

3Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan

4Department of Urologic Surgery, Vanderbilt University School of Medicine, TN 37232, USA

Correspondence to:

Zhenbang Chen, e-mail: zchen@mmc.edu

Keywords: PTEN, SKP2, JARID1B, TRAF6, histone modifications, prostate cancer

Received: September 02, 2014     Accepted: November 11, 2014     Published: December 23, 2014


Aberrant elevation of JARID1B and histone H3 lysine 4 trimethylation (H3K4me3) is frequently observed in many diseases including prostate cancer (PCa), yet the mechanisms on the regulation of JARID1B and H3K4me3 through epigenetic alterations still remain poorly understood. Here we report that Skp2 modulates JARID1B and H3K4me3 levels in vitro in cultured cells and in vivo in mouse models. We demonstrated that Skp2 inactivation decreased H3K4me3 levels, along with a reduction of cell growth, cell migration and malignant transformation of Pten/Trp53 double null MEFs, and further restrained prostate tumorigenesis of Pten/Trp53 mutant mice. Mechanistically, Skp2 decreased the K63-linked ubiquitination of JARID1B by E3 ubiquitin ligase TRAF6, thus decreasing JARID1B demethylase activity and in turn increasing H3K4me3. In agreement, Skp2 deficiency resulted in an increase of JARID1B ubiquitination and in turn a reduction of H3K4me3, and induced senescence through JARID1B accumulation in nucleoli of PCa cells and prostate tumors of mice. Furthermore, we showed that the elevations of Skp2 and H3K4me3 contributed to castration-resistant prostate cancer (CRPC) in mice, and were positively correlated in human PCa specimens. Taken together, our findings reveal a novel network of SKP2-JARID1B, and targeting SKP2 and JARID1B may be a potential strategy for PCa control.

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