title: 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.forename: Wei
authors.initials: W
authors.lastname: Qiang
authors.forename: Tianbo
authors.initials: T
authors.lastname: Jin
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.forename: Nongyue
authors.initials: N
authors.lastname: He
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006899:Mixed Function Oxygenases; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D044503:5-Methylcytosine; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D004268:DNA-Binding Proteins; D006899:Mixed Function Oxygenases; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C011865:5-hydroxymethylcytosine; C462539:TET1 protein, human; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one