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PRIMA-1 Selectively Induces Global DNA Demethylation in p53 Mutant-Type Thyroid Cancer Cells

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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.
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Document Type: Research Article

Publication date: July 1, 2014

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  • Journal of Biomedical Nanotechnology (JBN) is a peer-reviewed multidisciplinary journal providing broad coverage in all research areas focused on the applications of nanotechnology in medicine, drug delivery systems, infectious disease, biomedical sciences, biotechnology, and all other related fields of life sciences.
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