Transcriptional regulation of BNIP3 by Sp3 in prostate cancer
Transcriptional regulation of BNIP3 by Sp3 in prostate cancer
复制标题
前列腺癌中 Sp3 对 BNIP3 的转录调节。
DOI：
10.1002/pros.23029
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发表时间：
2015-10-01
期刊：
影响因子：
2.8
通讯作者：
Zhou, Qiao
中科院分区：
文献类型：
--
作者：
Huang, Ying;Shen, Pengfei;Zhou, Qiao
转录因子Sp3/Sp1在多种类型的癌症中表达，而BNIP3在前列腺癌中过表达。虽然已经证明BNIP3受HIF-1的转录调控，miR145的转录后调控，但我们之前的数据表明，在前列腺癌中可能还有其他转录因子调控BNIP3。本研究旨在探讨BNIP3的表达是否受Sp3/Sp1的直接调控。材料与方法生物信息学分析表明，BNIP3启动子含有多个潜在的Sp3/Sp1结合位点。然后通过双报告基因实验、ChIP和EMSA证明SP3可以通过结合预测位点来调控BNIP3的转录。通过MTT、TUNEL、流式细胞术检测SP3调控BNIP3对前列腺癌细胞增殖的生物学效应。结果Sp3基因与BNIP3在前列腺癌中的过表达呈正相关，Sp1基因与BNIP3过表达无关。Sp3主要结合到BNIP3启动子的Sp3结合位点（-624 ~ 615和-350 ~ 343），直接调控BNIP3的转录。RNA干扰敲低Sp3可抑制PC-3和DU145细胞生长，导致细胞凋亡。sp3依赖性BNIP3过表达可能是促进前列腺癌细胞增殖的重要机制。结论本研究首次提供了sp3依赖性BNIP3表达的直接证据。Sp3可能是BNIP3在前列腺癌中的主要转录调控因子，值得进一步研究。Sp3对BNIP3的调控可能成为前列腺癌治疗的新靶点。中华医学杂志（英文版），2015。(c) 2015 Wiley期刊公司
BACKGROUNDThe transcription factors Sp3/Sp1 are expressed in a various types of cancers and BNIP3 is overexpressed in prostate cancer. Although it has been demonstrated that BNIP3 is transcriptionally regulated by HIF-1 and is post-transcriptionally regulated by miR145, our previous data indicated that there might be some other transcription factors regulating BNIP3 in prostate cancer. This study is conducted to investigate whether BNIP3 expression is directly regulated by Sp3/Sp1 or not.MATERIALS AND METHODSBioinformatics analysis shows that BNIP3 promoter contains several potential Sp3/Sp1 binding sites. And then it is demonstrated that SP3 could regulate the BNIP3 transcriptionally by binding to the predicted sites by dual reporter gene assays, ChIP, and EMSA. The biological effects of SP3 regulating BNIP3 on prostate cancer cells proliferation are measured by MTT, TUNEL, and flow cytometry.RESULTSOur data show that Sp3 but not Sp1, is positively related to BNIP3 overexpression in prostate cancer. Sp3 can directly regulate BNIP3 transcription by mainly binding to the Sp3 binding sites (-624 approximate to-615 and -350 approximate to-343) of BNIP3 promoter. Knockdown of Sp3 by RNA interference could reduce cells growth and lead to cells apoptosis in PC-3 and DU145. Sp3-dependent BNIP3 overexpression might be an important mechanism to promote prostate cancer cells proliferation.CONCLUSIONThis is the first study to provide direct evidence of Sp3-dependent BNIP3 expression. Sp3 might be the major transcriptional regulator of BNIP3 in prostate cancer and it is worthy to further study. The regulation of BNIP3 by Sp3 may be a new cancer-specific therapeutic target in prostate cancer. Prostate 75:1556-1567, 2015. (c) 2015 Wiley Periodicals, Inc.