TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer
TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer
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DOI：
10.1038/s41388-017-0095-x
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发表时间：
2018-04-01
期刊：
影响因子：
8
通讯作者：
Inoue, Satoshi
中科院分区：
文献类型：
--
作者：
Takayama, Ken-ichi;Suzuki, Takashi;Inoue, Satoshi
雄激素受体（AR）及其下游信号的基因调控作用促进前列腺癌的生长。抑癌基因p53的异常功能对癌症的预后具有重要作用。我们之前发现雄激素治疗会将 p53 易位到细胞质。这种易位的机制取决于 SUMO E3 连接酶 RanBP2 与雄激素诱导的 GTP 酶激活蛋白结合蛋白 2 (G3BP2) 复合物对 p53 的苏酰化。在这里，我们鉴定出含有三联基序的蛋白 25 (TRIM25)/雌激素响应指蛋白 (Efp) 作为 G3BP2 蛋白复合物的新型相互作用伴侣。然后，我们证明 TRIM25 敲低导致 p53 下游激活，从而抑制 LNCaP 和 22Rv1 细胞的细胞周期并诱导细胞凋亡。相反，在 LNCaP 细胞中，多西他赛处理 TRIM25 的过表达可促进前列腺癌细胞增殖并抑制细胞凋亡。我们观察到，在 TRIM25 过表达的前列腺癌细胞中，G3BP2 介导的核输出机制降低了 p53 活性。我们还发现 TRIM25 对于 G3BP2/RanBP2 介导的 p53 修饰很重要。临床上，我们新证明TRIM25是前列腺癌患者的预后因素。 TRIM25 的表达与细胞质 p53 表达和 G3BP2 显着相关。此外，在前列腺癌小鼠异种移植模型中，TRIM25 敲除可导致肿瘤生长减少并增加 p53 活性。因此，我们的研究结果表明，TRIM25 的过度表达通过与 G3BP2 相互作用调节 p53 核输出机制来促进前列腺癌细胞增殖和细胞存活。
Prostate cancer growth is promoted by the gene regulatory action of androgen receptor (AR) and its downstream signals. The aberrant dysfunction of tumor suppressor p53 has an important role in the prognosis of cancer. We previously found that androgen treatments translocate p53 to the cytoplasm. The mechanism of this translocation depends on sumoylation of p53 by complex of SUMO E3 ligase RanBP2 with androgen-induced GTPase-activating protein-binding protein 2 (G3BP2). Here, we identified tripartite motif-containing protein 25 (TRIM25)/estrogen-responsive finger protein (Efp) as a novel interacting partner of G3BP2 protein complex. Then, we demonstrated that TRIM25 knockdown resulted in p53 downstream activation for cell cycle inhibition and apoptosis induction in LNCaP and 22Rv1 cells. In contrast, overexpression of TRIM25 promoted prostate cancer cell proliferation and inhibited apoptosis by docetaxel treatment in LNCaP cells. We observed that p53 activity was reduced by mechanism of G3BP2-mediated nuclear export in TRIM25-overexpressing prostate cancer cells. We also found TRIM25 is important for G3BP2/RanBP2-mediated p53 modification. Clinically, we newly demonstrated that TRIM25 is a prognostic factor for prostate cancer patients. Expression of TRIM25 is significantly associated with cytoplasmic p53 expression and G3BP2. Moreover, TRIM25 knockdown results in reduced tumor growth and increased p53 activity in the mouse xenograft model of prostate cancer. Thus, our findings show that overexpression of TRIM25 promoted prostate cancer cell proliferation and cell survival by modulating p53 nuclear export mechanism with G3BP2 interaction.