Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth.
Tricho-rhino-phalangeal syndrome 1 protein functions as a scaffold required for ubiquitin-specific protease 4-directed histone deacetylase 2 de-ubiquitination and tumor growth.
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毛犀指骨综合征 1 蛋白充当泛素特异性蛋白酶 4 指导的组蛋白脱乙酰酶 2 去泛素化和肿瘤生长所需的支架。
DOI：
10.1186/s13058-018-1018-7
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发表时间：
2018-08-02
期刊：
影响因子：
--
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang J;Wu L;Liu W;Wei G;Gong X;Liu Y;Ma Z;Ma F;Thiery JP;Chen L
背景尽管许多研究报道了唯一报道的非典型加塔转录因子-方法采用过表达和敲低TRPS 1的方法检测TRPS 1对组蛋白去乙酰化酶2（HDAC 2）的影响。蛋白水平与乳腺癌细胞增殖的关系。此外，RT-qRCR，荧光素酶报告基因测定和RNA测序用于转录检测。使用H4 K16 ac抗体结合qPCR的染色质免疫沉淀（ChIP）用于测定靶基因中的H4 K16 ac水平。此外，在体外细胞增殖试验和在体内肿瘤异种移植物被用来检测TRPS 1对肿瘤growth.ResultsWe发现，TRPS 1支架招聘和增强之间的相互作用USP 4和HDAC 2导致HDAC 2去泛素化和H4 K16去乙酰化。我们检测到TRPS 1-USP 4-HDAC 2轴对一组细胞生长相关基因的抑制，表明其在肿瘤生长中是必需的。在体外和体内实验证实，silencingTRPS 1减少肿瘤生长，而过表达的HDAC 2恢复tumor growth.ConclusionOur研究破译的TRPS 1-USP 4-HDAC 2轴作为一种新的机制，有助于肿瘤生长。值得注意的是，我们的结果揭示了TRPS 1在USP 4指导的HDAC 2去遍在蛋白化中的支架功能，并为TRPS 1、遍在蛋白和组蛋白修饰系统之间导致肿瘤生长的串扰提供了新的机制见解。
BackgroundAlthough numerous studies have reported that tricho-rhino-phalangeal syndrome type I (TRPS1) protein, the only reported atypical GATA transcription factor, is overexpressed in various carcinomas, the underlying mechanism(s) by which it contributes to cancer remain unknown.MethodsBoth overexpression and knockdown of TRPS1 assays were performed to examine the effect of TRPS1 on histone deacetylase 2 (HDAC2) protein level and luminal breast cancer cell proliferation. Also, RT-qRCR, luciferase reporter assay and RNA-sequencing were used for transcription detection. Chromatin immunoprecipitation (ChIP) using H4K16ac antibody in conjunction with qPCR was used for determining H4K16ac levels in targeted genes. Furthermore, in vitro cell proliferation assay and in vivo tumor xenografts were used to detect the effect of TRPS1 on tumor growth.ResultsWe found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation. We detected repression of a set of cellular growth-related genes by the TRPS1-USP4-HDAC2 axis indicating it is essential in tumor growth. In vitro and in vivo experiments confirmed that silencingTRPS1reduced tumor growth, whereas overexpression of HDAC2 restored tumor growth.ConclusionOur study deciphered the TRPS1-USP4-HDAC2 axis as a novel mechanism that contributes to tumor growth. Significantly, our results revealed the scaffolding function of TPRS1 in USP4-directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth.
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