The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas
The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas
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可转导的 TAT-RIZ1-PR 蛋白在人恶性脑膜瘤中发挥组蛋白甲基转移酶活性和肿瘤抑制功能
DOI：
10.1016/j.biomaterials.2015.03.058
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发表时间：
2015-07-01
期刊：
影响因子：
14
通讯作者：
Jin, Wei-Lin
中科院分区：
文献类型：
--
作者：
Ding, Mao-Hua;Wang, Zhen;Jin, Wei-Lin
恶性脑膜瘤是一种罕见的脑膜瘤亚型，往往有术后复发。已经做出了重大努力来确定功能性治疗靶点，以阻止这种侵袭性癌症的生长。我们最近发现RIZ 1在高级别脑膜瘤中下调，RIZ 1过表达抑制IOMM-Lee恶性脑膜瘤细胞系的增殖，同时促进细胞凋亡。在这份报告中，我们表明，N-末端PR结构域RIZ 1单独具有生长抑制活性和抗癌活性的原代人脑膜瘤细胞。有趣的是，这些作用似乎依赖于不同的RIZ 1蛋白水平。可转导的TAT-RIZ 1-PR蛋白在裸鼠模型中也能抑制脑膜瘤的生长。我们进一步证明，PR蛋白发挥组蛋白甲基转移酶活性。TAT-RIZ 1-PR处理的人恶性脑膜瘤细胞的微阵列分析揭示了969个差异表达基因和848个选择性剪接外显子。此外，c-Myc和TXNIP，H3 K9甲基化的两个推定的下游靶点，可能参与调节RIZ 1肿瘤抑制作用。然后在原发性脑膜瘤细胞和人类肿瘤样品中验证RIZ 1和c-Myc之间的相互关系。这些发现为RIZ 1肿瘤抑制机制提供了新的见解，并表明TAT-RIZ 1-PR蛋白是晚期脑膜瘤潜在的新表观遗传治疗剂。(C)2015爱思唯尔有限公司版权所有。
Malignant meningiomas are a rare meningioma subtype and tend to have post-surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N-terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1-PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas. (C) 2015 Elsevier Ltd. All rights reserved.