Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer.
Overexpression of DNA 5'-cytosine-methyltransferases (DNMT), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, the mechanism of DNMT overexpression remains unclear. Here, we showed that wild-type p53 negatively regulated DNMT1 expression by forming a complex with specificity protein 1 (Sp1) protein and chromatin modifiers on the DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or corepressor. Low level of exogenous Sp1 enhanced the repressive activity of endogenous p53 on the DNMT1 promoter whereas high level of Sp1 upregulated DNMT1 gene expression level in A549 (p53 wild-type) cells. In H1299 (p53 null) cells, exogenous Sp1 induced DNMT1 expression in a dose-dependent manner. We also discovered a new mechanism whereby high level of Sp1, via its COOH-terminal domain, induced interaction between p53 and MDM2, resulting in degradation of p53 by MDM2-mediated ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation (P = 0.014) and high expression of Sp1 protein (P = 0.006). In addition, patients with overexpression of both DNMT1 and Sp1 proteins showed poor prognosis (P = 0.037). Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with gain of transcriptional activation of Sp1 and/or loss of repression of p53. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis.
Lin
Ruo-Kai
RK
Department of Pharmacology, College of Medicine, and Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan, ROC.
Wu
Chiu-Yi
CY
Chang
Jer-Wei
JW
Juan
Li-Jung
LJ
Hsu
Han-Shui
HS
Chen
Chih-Yi
CY
Lu
Yun-Yueh
YY
Tang
Yen-An
YA
Yang
Yi-Chieh
YC
Yang
Pan-Chyr
PC
Wang
Yi-Ching
YC
D044503:5-Methylcytosine / Q000378:metabolism; D001665:Binding Sites; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D016329:Sp1 Transcription Factor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044503:5-Methylcytosine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2