Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin.
Negative regulation of the oncogenic transcription factor FoxM1 by thiazolidinediones and mithramycin.
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DOI：
10.4161/cbt.9.12.11710
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发表时间：
2010-06-15
影响因子：
3.6
通讯作者：
Tyner AL
中科院分区：
文献类型：
--
作者：
Petrovic V;Costa RH;Lau LF;Raychaudhuri P;Tyner AL
叉头盒转录因子FoxM1调控促进细胞周期进展的基因表达，在肝、肺、前列腺和结直肠肿瘤的发生发展中发挥重要作用。噻唑烷二酮类（TZDs）可激活过氧化物酶体增殖体激活受体γ (PPARγ)，这是一种配体激活的核受体转录因子。我们发现用TZDs处理人肝癌细胞系HepG2和PLC/PRF/5细胞可抑制FoxM1基因的表达。在FoxM1上游- 10 kb的启动子中没有检测到PPARγ/类视黄醇X受体（RXR）一致的DNA结合位点，并且PPARγ的敲低对TZD介导的FoxM1表达下调没有影响。此前，其他研究表明，PPARγ激动剂抑制Sp1转录因子的表达和dna结合活性。这里我们发现Sp1结合到FoxM1启动子区域并正向调节FoxM1的转录，而米特霉素，一种特异性结合DNA中富含GC序列并抑制Sp1活性的化疗药物，抑制FoxM1的表达。我们的数据表明，TZD介导的Sp1抑制是FoxM1基因表达下调的原因。TZDs对FoxM1表达的抑制为TZD介导的恶性肿瘤细胞生长的负调控提供了新的机制。FoxM1在癌细胞中的表达和活性可以通过PPARγ激动剂或抗肿瘤抗生素米霉素来靶向。
The Forkhead Box transcription factor FoxM1 regulates expression of genes that promote cell cycle progression, and it plays essential roles in the development of liver, lung, prostate and colorectal tumors. Thiazolidinediones (TZDs) activate the peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated nuclear receptor transcription factor. We found that treatment of the human hepatoma cell lines HepG2 and PLC/PRF/5 cells with TZDs leads to inhibition of FoxM1 gene expression. No PPARγ/retinoid X receptor (RXR) consensus DNA binding sites were detected in the FoxM1 promoter extending to −10 kb upstream, and knockdown of PPARγ had no impact on TZD mediated downregulation of FoxM1 expression. Previously, others showed that PPARγ agonists inhibit the expression and DNA-binding activity of the Sp1 transcription factor. Here we show that Sp1 binds to the FoxM1 promoter region and positively regulates FoxM1 transcription, while mithramycin, a chemotherapy drug that specifically binds GC rich sequences in the DNA and inhibits activities of Sp1, inhibits expression of FoxM1. Our data suggest that TZD mediated suppression of Sp1 is responsible for downregulation of FoxM1 gene expression. Inhibition of FoxM1 expression by TZDs provides a new mechanism for TZD mediated negative regulation of cancer cell growth. FoxM1 expression and activity in cancer cells can be targeted using PPARγ agonists or the anti-neoplastic antibiotic mithramycin.
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影响因子：
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