The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.
The oncoprotein HBXIP activates transcriptional coregulatory protein LMO4 via Sp1 to promote proliferation of breast cancer cells.
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癌蛋白HBXIP通过Sp1激活转录共调节蛋白LMO4促进乳腺癌细胞增殖
DOI：
10.1093/carcin/bgs399
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发表时间：
2013-04
期刊：
影响因子：
4.7
通讯作者：
Ye L
中科院分区：
文献类型：
--
作者：
Yue L;Li L;Liu F;Hu N;Zhang W;Bai X;Li Y;Zhang Y;Fu L;Zhang X;Ye L
乙肝X-相互作用蛋白(HBXIP)是一种重要的癌蛋白，在肿瘤的发生发展中起着关键作用。在这项研究中，我们报道了HBXIP激活LIM-Only Protein 4(LMO4)，这是一种转录共调节蛋白，促进细胞增殖。我们观察到临床乳腺癌组织中HBXIP和LMO4的信使RNA(MRNA)表达水平呈正相关。我们进一步证实，HBXIP在启动子、mRNA和蛋白水平上调LMO4在MCF-7和LM-MCF-7乳腺癌细胞系中的表达。HBXIP通过LMO4上调LMO4下游效应因子细胞周期蛋白D1和细胞周期蛋白E的表达。染色质免疫沉淀(ChIP)实验表明HBXIP能够与LMO4启动子区域相互作用。凝胶迁移率改变分析表明，HBXIP位于含有Sp1结合元件的LMO4启动子的-237/-206区域。LMO4启动子中Sp1结合位点的突变阻碍了HBXIP与启动子的相互作用。免疫共沉淀、芯片和荧光素酶报告基因分析表明，HBXIP通过与Sp1结合激活了LMO4启动子。在功能方面，通过流式细胞仪、3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium溴化物、5-乙炔基-2‘-脱氧尿苷(EDU)掺入实验和动物移植实验证明，HBXIP通过上调LMO4在体内外促进乳腺癌细胞的增殖。因此，我们认为癌蛋白HBXIP能够通过转录因子Sp1激活转录共调控蛋白LMO4，从而促进乳腺癌细胞的增殖。HBXIP可能是肿瘤发生发展过程中激活转录的驱动基因。
Hepatitis B X-interacting protein (HBXIP) is an important oncoprotein that plays critical role in the development of cancer. In this study, we report that HBXIP activates LIM-only protein 4 (LMO4), a transcriptional coregulatory protein, in promotion of cell proliferation. We observed that the messenger RNA (mRNA) expression levels of HBXIP were positively associated with those of LMO4 in clinical breast cancer tissues. We further identified that HBXIP upregulated LMO4 at the levels of promoter, mRNA and protein in MCF-7 and LM-MCF-7 breast cancer cell lines. The expression of cyclin D1 and cyclin E, downstream effectors of LMO4, could be upregulated by HBXIP through LMO4. Then, chromatin immunoprecipitation (ChIP) assay revealed that HBXIP was able to interact with the promoter region of LMO4. Electrophoretic mobility shift assay showed that HBXIP occupied the -237/-206 region of LMO4 promoter containing Sp1 binding element. The mutant of Sp1 binding site in the LMO4 promoter impeded the interaction of HBXIP with the promoter. Co-immunoprecipitation, ChIP and luciferase reporter gene assays showed that HBXIP activated LMO4 promoter through binding to Sp1. In function, flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays and animal transplantation assays demonstrated that HBXIP-enhanced cell proliferation of breast cancer through upregulating LMO4 in vitro and in vivo. Thus, we concluded that oncoprotein HBXIP is able to activate the transcriptional coregulatory protein LMO4 through transcription factor Sp1 in promotion of proliferation of breast cancer cells. HBXIP may serve as a driver gene to activate transcription in the development of cancer.
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