Negative Regulation of the Oncogenic Transcription Factor FoxM1 by Thiazolidinediones and Mithramycin

Overview

Journal Cancer Biol Ther

Specialties Oncology
Pharmacology

Date 2010 Apr 8

PMID 20372080

Citations 24

Authors

Vladimir Petrovic

Robert H Costa

Lester F Lau

Pradip Raychaudhuri

Angela L Tyner

Affiliations

Soon will be listed here.

Abstract

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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References

Park H, Carr J, Wang Z, Nogueira V, Hay N, Tyner A . FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J. 2009; 28(19):2908-18. PMC: 2760115. DOI: 10.1038/emboj.2009.239. View

Gee J, Blume S, SNYDER R, Ray R, Miller D . Triplex formation prevents Sp1 binding to the dihydrofolate reductase promoter. J Biol Chem. 1992; 267(16):11163-7. View

Adami G, Ye H . Future roles for FoxM1 inhibitors in cancer treatments. Future Oncol. 2007; 3(1):1-3. DOI: 10.2217/14796694.3.1.1. View

Westendorf J, Zwicker J, Burkhardt H, Henriksson M, Muller R, Pirollet F . Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation. Oncogene. 1999; 18(41):5620-30. DOI: 10.1038/sj.onc.1202967. View

Kalinichenko V, Major M, Wang X, Petrovic V, Kuechle J, Yoder H . Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 2004; 18(7):830-50. PMC: 387422. DOI: 10.1101/gad.1200704. View

Laoukili J, Stahl M, Medema R . FoxM1: at the crossroads of ageing and cancer. Biochim Biophys Acta. 2006; 1775(1):92-102. DOI: 10.1016/j.bbcan.2006.08.006. View

Yu J, Qiao L, Zimmermann L, Ebert M, Zhang H, Lin W . Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo. Hepatology. 2005; 43(1):134-43. DOI: 10.1002/hep.20994. View

Palmer C, Hsu M, Griffin H, Johnson E . Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem. 1995; 270(27):16114-21. DOI: 10.1074/jbc.270.27.16114. View

Sarraf P, Mueller E, Jones D, KING F, DeAngelo D, Partridge J . Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998; 4(9):1046-52. DOI: 10.1038/2030. View

10.

Gartel A . FoxM1 inhibitors as potential anticancer drugs. Expert Opin Ther Targets. 2008; 12(6):663-5. DOI: 10.1517/14728222.12.6.663. View

11.

Sahi J, Black C, Hamilton G, Zheng X, Jolley S, Rose K . Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos. 2003; 31(4):439-46. DOI: 10.1124/dmd.31.4.439. View

12.

Kliewer S, Lehmann J, Milburn M, Willson T . The PPARs and PXRs: nuclear xenobiotic receptors that define novel hormone signaling pathways. Recent Prog Horm Res. 1999; 54:345-67; discussion 367-8. View

13.

Wang I, Meliton L, Tretiakova M, Costa R, Kalinichenko V, Kalin T . Transgenic expression of the forkhead box M1 transcription factor induces formation of lung tumors. Oncogene. 2008; 27(30):4137-49. DOI: 10.1038/onc.2008.60. View

14.

Major M, Lepe R, Costa R . Forkhead box M1B transcriptional activity requires binding of Cdk-cyclin complexes for phosphorylation-dependent recruitment of p300/CBP coactivators. Mol Cell Biol. 2004; 24(7):2649-61. PMC: 371108. DOI: 10.1128/MCB.24.7.2649-2661.2004. View

15.

Kubota T, Koshizuka K, Williamson E, Asou H, Said J, Holden S . Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res. 1998; 58(15):3344-52. View

16.

Yao J, Wang L, Wei D, Gong W, Hassan M, Wu T . Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin Cancer Res. 2004; 10(12 Pt 1):4109-17. DOI: 10.1158/1078-0432.CCR-03-0628. View

17.

Korver W, Roose J, Clevers H . The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res. 1997; 25(9):1715-9. PMC: 146663. DOI: 10.1093/nar/25.9.1715. View

18.

Ye H, Holterman A, Yoo K, Franks R, Costa R . Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S phase. Mol Cell Biol. 1999; 19(12):8570-80. PMC: 84981. DOI: 10.1128/MCB.19.12.8570. View

19.

Loi C, Young M, Randinitis E, Vassos A, Koup J . Clinical pharmacokinetics of troglitazone. Clin Pharmacokinet. 1999; 37(2):91-104. DOI: 10.2165/00003088-199937020-00001. View

20.

Wang L, Guan X, Zhang J, Jia Z, Wei D, Li Q . Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models. Int J Oncol. 2008; 33(1):161-7. View