Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
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DOI：
10.1002/ijc.24761
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发表时间：
2010-01-15
影响因子：
6.4
通讯作者：
Archer, Michael C.
中科院分区：
文献类型：
--
作者：
Lu, Suying;Archer, Michael C.
癌症表达高水平的脂肪酸合酶（FAS），它们从中获得脂肪酸用于膜生物合成以维持细胞增殖。癌细胞如何协调从头脂肪生成和增殖尚未研究。转录因子Sp1、Sp3和Sp 4在多种癌症中过表达，并通过与富含GC的Sp1结合位点相互作用来调节基因表达。编码FAS和细胞周期蛋白如CDC 25 A的基因在其启动子中含有Sp1结合位点。我们通过RNA干扰证实了Sp1、Sp3和Sp 4都在调节人乳腺癌细胞中CDC 25 A的表达和增殖中起作用。然而，只有Sp1也调节FAS。此外，光神霉素，它阻止Sp1结合位点，减少增殖，抑制CDC 25 A和FAS的表达和减少Sp1的结合，这些基因的启动子通过ChIP测定评估。相反，17 β-雌二醇（E-2）增加增殖和CDC 25 A和FAS的表达，沿着增加Sp1与2个基因启动子的结合。此外，我们发现，固醇调节元件结合蛋白-1c（SREBP-1c）的表达也受到Sp1的调节，该蛋白是唯一被证明可调节癌细胞中脂肪生成酶基因的转录因子。最后，我们证明了Sp1在维持结肠癌和前列腺癌细胞的增殖和FAS表达中起作用。总的来说，这些观察结果表明，Sp1协调调节癌细胞中的从头，脂肪生成和增殖。
Cancers express high levels of fatty acid synthase (FAS) from which they derive fatty acids for membrane biosynthesis to sustain cell proliferation. How cancer cells coordinate de novo lipogenesis and proliferation has not been investigated. Transcription factors Sp1, Sp3 and Sp4 are overexpressed in a variety of cancers and regulate gene expression by interacting with GC-rich Sp1 binding sites. Genes encoding FAS and cell cycle proteins such as CDC25A contain Sp1 binding sites in their promoters. We demonstrate by RNA interference that Sp1, Sp3 and Sp4 all play a role in regulating CDC25A expression and proliferation in human breast cancer cells. Only Sp1, however, also regulates FAS. Furthermore, mithramycin, which blocks Sp1 binding sites, decreased proliferation, inhibited CDC25A and FAS expression and reduced binding of Sp1 to the promoters of these genes as assessed by ChIP assays. Conversely, 17 beta-estradiot (E-2) increased proliferation and CDC25A and FAS expression along with increased binding of Sp1 to the promoters of the 2 genes. In addition, we showed that the expression of sterol regulatory element-binding protein-1c (SREBP-1c), the only transcription factor that has been shown to regulate genes of lipogenic enzymes in cancer cells, is also regulated by Sp1. Finally, we demonstrated that Sp1 plays a role in sustaining proliferation and FAS expression in colon as well as prostate cancer cells. Overall, these observations suggest that Sp1 coordinately regulates de novo, lipogenesis and proliferation in cancer cells.