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Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells
Author(s) -
Lu Suying,
Archer Michael C.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24761
Subject(s) - promoter , cell growth , biology , sp1 transcription factor , lipogenesis , transcription factor , cancer cell , cdc25a , cancer research , sterol regulatory element binding protein , gene expression , microbiology and biotechnology , gene , cell cycle , cancer , biochemistry , genetics , cell cycle checkpoint
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, 17β‐estradiol (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.