Statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are broadly used to improve hypercholesterolemia. Recently, they are reported to have beneficial effects on certain cancers by inhibiting the histone deacetylases (HDACs) activity. However, the molecular mechanism underlying statins-induced cancer cell death remains unclear. The post-translational modifications of p53 family proteins (p53, p63 and p73) enable them to transactivate p53-responsive genes, and induce cell cycle arrest or apoptosis. Moreover, a number of microRNAs (miRNAs) have been shown to function as transcriptional targets of p53 in promoting apoptosis. The question of p53/p63/p73 regulating the miRNAs has not been addressed in depth so far. Whether p53 family proteins and miRNAs play an essential role in statins-induced colorectal cancer cell death remains to be established. In our preliminary studies, we found that statins including simvastatin decreased cell viability and induced apoptosis in colorectal cancer cells. Simvastatin caused p53 phosphorylation and acetylation in HCT116 colorectal cancer cells. Simvastatin-decreased cell viability was restored in p53 knockout HCT116 cells. Furthermore, simvastatin increased the binding of p53, p63 and p73 to the promoter region of miRNA34a. Simvastatin also increased miR34a promoter luciferase activity. This project aims to establish the causal role of p53 family proteins and miRNAs in statins-induced colorectal cancer cell death. The central hypothesis of this project is that statins inhibition of HDACs affects the post-translational modifications of p53 family proteins, which leads to miRNA34a expression and subsequent colorectal cancer cell death. Because the clinical application of statins has been well characterized, understanding the statins’ actions in cancer cell will aid in future development of selective-targeting strategies for statins to prevent cancer.
|Effective start/end date||8/1/12 → 7/31/13|
- microRNA (miRNA)
- histone deacetylase (HDAC)
- colorectal cancer
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