SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination.
SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination.
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DOI：
10.18632/oncotarget.2718
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发表时间：
2015-01-20
期刊：
影响因子：
--
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Lu W;Liu S;Li B;Xie Y;Adhiambo C;Yang Q;Ballard BR;Nakayama KI;Matusik RJ;Chen Z
JARID1B和组蛋白H3赖氨酸4三甲基化(H3K4me3)在前列腺癌(Pca)等多种疾病中普遍存在，但通过表观遗传学改变调控JARID1B和H3K4me3的机制尚不清楚。在此，我们报道了Skp2在体外培养细胞和体内小鼠模型中调节JARID1B和H3K4me3的水平。我们发现，Skp2失活降低了H3K4me3的水平，并减少了Pten/Trp53双零MEF的细胞生长、细胞迁移和恶变，进一步抑制了Pten/Trp53突变小鼠的前列腺癌的发生。在机制上，Skp2通过E3泛素连接酶TRAF6降低K63连接的JARID1B泛素化，从而降低JARID1B去甲基酶活性，进而增加H3K4me3。同样，Skp2缺乏导致JARID1B泛素化增加，进而导致H3K4me3减少，并通过JARID1B在前列腺癌细胞和小鼠前列腺肿瘤的核仁中积聚而诱导衰老。此外，我们还发现，Skp2和H3K4me3的升高与小鼠的去势抵抗前列腺癌(CRPC)有关，并且在人类前列腺癌标本中呈正相关。综上所述，我们的发现揭示了一个新的Skp2-JARID1B网络，靶向Skp2和JARID1B可能是一种潜在的PCa控制策略。
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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DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
7.3
作者：
Chen Z;Carracedo A;Lin HK;Koutcher JA;Behrendt N;Egia A;Alimonti A;Carver BS;Gerald W;Teruya-Feldstein J;Loda M;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
11.8
作者：
Nakayama, K;Nagahama, H;Nakayama, KI
通讯作者：
Nakayama, KI
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
--
作者：
Ellis L;Ku SY;Ramakrishnan S;Lasorsa E;Azabdaftari G;Godoy A;Pili R
通讯作者：
Pili R