PRIMA-1 selectively induces global DNA demethylation in p53 mutant-type thyroid cancer cells.

Abstract

The p53 tumor suppressor pathway blocks carcinogenesis by triggering apoptosis and cellular senescence in response to oncogenic stress. Over 50% of human cancers including thyroid cancer carry loss-of-function mutations in the p53 gene. Recently, the identification of mutant p53-reactivating small molecules such as PRIMA-1 (p53 reactivation and induction of massive apoptosis) renders possibilities for the development of more efficient anticancer drugs. Although PRIMA-1 has been widely used for cancer therapy and exhibits a promising anticancer activity, its biological effect, particularly the epigenetic aspect, remains to be well elucidated. The present study attempts to explore the effect of PRIMA-1 on DNA methylation in a panel of thyroid cancer cell lines using luminometric methylation assay (LUMA). Our results showed that only p53 mutant-type cells were inhibited upon PRIMA-1 treatment. Conversely, p53 wild-type cells were non-sensitive to PRIMA-1. Moreover, our data demonstrated that PRIMA-1 selectively induced significant global DNA demethylation in p53 mutant-type cells. Mechanically, PRIMA-1 induced global DNA demethylation in these cells mainly through inhibiting the expression of DNA methyltransferase (DNMT) 1, 3a and 3b, and upregulating the expression of GADD45a. Notably, PRIMA-1 dramatically increased the expression of the ten-eleven translocation (TET) family of 5mC-hydroxylases, particularly TET1, in p53 mutant-type cells, further contributing to DNA demethylation. Thus, this study uncovered a previously unrecognized and prominent biological effect of PRIMA-1 through which it can cause global DNA demethylation in p53 mutant-type cancer cells mainly by rescuing the function of mutant p53 protein.

• Authors: Wei Qiang, Tianbo Jin, Qi Yang, Wei Liu, Shu Liu, Meiju Ji, Nongyue He, Chao Chen, Bingyin Shi, Peng Hou
• Journal: Journal of biomedical nanotechnology (J Biomed Nanotechnol) Vol. 10 Issue 7 Pg. 1249-58 (Jul 2014) ISSN: 1550-7033 [Print] United States
• PMID: 24804545 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aza Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• DNA-Binding Proteins
• GADD45A protein, human
• Nuclear Proteins
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• 5-hydroxymethylcytosine
• 5-Methylcytosine
• Cytosine
• Mixed Function Oxygenases
• TET1 protein, human
• DNA (Cytosine-5-)-Methyltransferases
• 2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one

Topics

• 5-Methylcytosine (analogs & derivatives)
• Aza Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cytosine (analogs & derivatives, metabolism)
• DNA (Cytosine-5-)-Methyltransferases (metabolism)
• DNA Methylation (drug effects, genetics)
• DNA-Binding Proteins (genetics, metabolism)
• Down-Regulation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mixed Function Oxygenases
• Models, Biological
• Mutation (genetics)
• Nuclear Proteins (metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Thyroid Neoplasms (drug therapy, enzymology, genetics, pathology)
• Tumor Suppressor Protein p53 (genetics)
• Up-Regulation (drug effects)
• bcl-2-Associated X Protein (metabolism)