SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination

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

doi:10.18632/oncotarget.2718

Wenfu Lu, Shenji Liu + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.2718

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Abstract

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.

Highlights

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American males [1]
To explore the role of SKP2 on epigenetics and the relevance on PCa progression in vivo, we wished to investigate whether Skp2 deficiency suppresses prostate tumorigenesis through affecting the functional coupling of JARID1B and H3K4me3 in mouse models
We focused on JARID1B as it controls H3K4me3 and its abnormal upregulation is frequently observed in PCa [17,18,19,20]

Summary

Introduction

Prostate cancer (PCa) is the second leading cause of cancer-related deaths in American males [1]. Emerging evidence revealed that SKP2 plays an essential role in cell cycle proliferation, cellular senescence, cancer progression, and metastasis [6, 8,9,10]. This phenomenon is likely a result of degrading the downstream substrates in cell cycles such as p27 [8, 11]. SKP2 affects the expression of proteins other than its substrates such as ATF4 [8], RhoA and Miz1 [10] and C-Myc [12, 13], suggesting its essential roles independent of E3 ligase in PCa. Recent studies indicated that SKP2 has novel www.impactjournals.com/oncotarget functions in glycolysis and tumorigenesis through the regulation of AKT ubiquitination in human breast cancer [14]. The role of SKP2 on the regulation of histone modifications in human PCa still remains elusive

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