Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer

Ruo Kai Lin, Chiu Yi Wu, Jer Wei Chang, Li Jung Juan, Han Shui Hsu, Chih Yi Chen, Yun Yueh Lu, Yen An Tang, Yi Chieh Yang, Pan Chyr Yang, Yi Ching Wang

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5807-5817
Number of pages11
JournalCancer Research
Volume70
Issue number14
DOIs
Publication statusPublished - Jul 15 2010
Externally publishedYes

Fingerprint

Methyltransferases
Lung Neoplasms
DNA
Proteins
DNA (Cytosine-5-)-Methyltransferase
Co-Repressor Proteins
Null Lymphocytes
Ubiquitination
Cytosine
Tumor Suppressor Genes
Epigenomics
Transcriptional Activation
Chromatin
Carcinogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lin, R. K., Wu, C. Y., Chang, J. W., Juan, L. J., Hsu, H. S., Chen, C. Y., ... Wang, Y. C. (2010). Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Research, 70(14), 5807-5817. https://doi.org/10.1158/0008-5472.CAN-09-4161

Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. / Lin, Ruo Kai; Wu, Chiu Yi; Chang, Jer Wei; Juan, Li Jung; Hsu, Han Shui; Chen, Chih Yi; Lu, Yun Yueh; Tang, Yen An; Yang, Yi Chieh; Yang, Pan Chyr; Wang, Yi Ching.

In: Cancer Research, Vol. 70, No. 14, 15.07.2010, p. 5807-5817.

Research output: Contribution to journalArticle

Lin, RK, Wu, CY, Chang, JW, Juan, LJ, Hsu, HS, Chen, CY, Lu, YY, Tang, YA, Yang, YC, Yang, PC & Wang, YC 2010, 'Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer', Cancer Research, vol. 70, no. 14, pp. 5807-5817. https://doi.org/10.1158/0008-5472.CAN-09-4161
Lin, Ruo Kai ; Wu, Chiu Yi ; Chang, Jer Wei ; Juan, Li Jung ; Hsu, Han Shui ; Chen, Chih Yi ; Lu, Yun Yueh ; Tang, Yen An ; Yang, Yi Chieh ; Yang, Pan Chyr ; Wang, Yi Ching. / Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. In: Cancer Research. 2010 ; Vol. 70, No. 14. pp. 5807-5817.
@article{e04c793c7a6c4723a58e21a33384b105,
title = "Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer",
abstract = "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.",
author = "Lin, {Ruo Kai} and Wu, {Chiu Yi} and Chang, {Jer Wei} and Juan, {Li Jung} and Hsu, {Han Shui} and Chen, {Chih Yi} and Lu, {Yun Yueh} and Tang, {Yen An} and Yang, {Yi Chieh} and Yang, {Pan Chyr} and Wang, {Yi Ching}",
year = "2010",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-09-4161",
language = "English",
volume = "70",
pages = "5807--5817",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer

AU - Lin, Ruo Kai

AU - Wu, Chiu Yi

AU - Chang, Jer Wei

AU - Juan, Li Jung

AU - Hsu, Han Shui

AU - Chen, Chih Yi

AU - Lu, Yun Yueh

AU - Tang, Yen An

AU - Yang, Yi Chieh

AU - Yang, Pan Chyr

AU - Wang, Yi Ching

PY - 2010/7/15

Y1 - 2010/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77955015091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955015091&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-4161

DO - 10.1158/0008-5472.CAN-09-4161

M3 - Article

VL - 70

SP - 5807

EP - 5817

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 14

ER -