SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination

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.

Histone H3K4 trimethylation: dynamic interplay with pre-mRNA splicing

“…Further, the KDM5 family members undergo numerous PTMs including acetylation, ubiquitination and phosphorylation (Hornbeck et al, 2015), and these PTMs could regulate activity and/or location. For example, K63-linked ubiquitination of KDM5B is (Lu et al, 2015). The authors of this study suggest that a combinatory approach of inhibiting SKP2 and KDM5B may be an effective therapy in treating castration resistant prostate cancer (Lu et al, 2015).…”

“…For example, K63-linked ubiquitination of KDM5B is (Lu et al, 2015). The authors of this study suggest that a combinatory approach of inhibiting SKP2 and KDM5B may be an effective therapy in treating castration resistant prostate cancer (Lu et al, 2015).…”

SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer

“…12,13 We recently reported that SKP2 ablation elevates the ubiquitination and activity of JARID1B, a histone modification demethylase, to decrease histone H3 lysine 4 trimethylation (H3K4me3) levels in suppression of PCa tumorigenesis. 2 That study provided a clue on the role of SKP2 on histone modifications and the epigenetic alterations in PCa. Although levels of SKP2 and Enhancer of zeste homolog 2 (EZH2) are highly associated with aggressive features of human PCa, 1,14 it remains unclear whether SKP2 determines the levels of histone H3 lysine 27 trimethylation (H3K27me3) state by modulating EZH2.…”

“…1,2 Mechanistic explanations on the dysregulation of histone modifications are needed in order to precisely target the key epigenetic regulators for PCa treatment. S-phase kinase-associated protein 2 (SKP2), a member of the F-box protein family, forms SKP2–SCF complex with SKP1, Cullin-1 and RBX1 to act as a ubiquitin ligase for protein ubiquitination and degradation of tumor suppressors and other proteins.…”

The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2

“…More recently, Skp2 has been shown to exhibit homeostatic regulation of tumor suppressor DAB2IP and suppression of JARID1B demethylase activity in prostate carcimona. 33,34 Likewise cullin1 based E3 ubiquitin ligases, cullin4-based E3 ubiquitin ligases also play an important role in cell proliferation, DNA damage repair 7 and ubiquitylation of histone 10 via different DCAFs like Cul4-DDB1-Det1-Cop1 regulate intracellular c-jun level. 35 The present study showed that TRUSS expression peaked during the G1 phase of cell cycle and as the cells progress from G1 to S phase TRUSS level gets down-regulated coinciding with Skp2 expression.…”