Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target

Kavitha Ramachandran, Gopal Gopisetty, Edna Gordian, Loida Navarro, Christiane Hader, Isildinha Reis, Wolfgang A. Schulz, Rakesh Singal

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45α) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45α in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45α in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45α expression in these cells. The 5' 4 CpG region was also frequently methylated in prostate cancer tissues. Meth-ylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2 -) led to a significantly increased expression of GADD45α (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45α in Du145 cells by recombinant expression of GADD45α or pretreatment with 5-azacytidine. Our results show that GADD45α is epigenetically repressed and is a potential target for treatment of prostate cancer. [Cancer Res 2009;69(4):1527-35]

Original languageEnglish
Pages (from-to)1527-1535
Number of pages9
JournalCancer Research
Volume69
Issue number4
DOIs
StatePublished - Feb 15 2009

Fingerprint

docetaxel
Methylation
Prostatic Neoplasms
Therapeutics
Up-Regulation
Gene Expression
Azacitidine
Drug Therapy
Methyltransferases
Genetic Promoter Regions
DNA Damage
Neoplasms
Carrier Proteins
Cell Proliferation
Cell Line
DNA
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target. / Ramachandran, Kavitha; Gopisetty, Gopal; Gordian, Edna; Navarro, Loida; Hader, Christiane; Reis, Isildinha; Schulz, Wolfgang A.; Singal, Rakesh.

In: Cancer Research, Vol. 69, No. 4, 15.02.2009, p. 1527-1535.

Research output: Contribution to journalArticle

Ramachandran, Kavitha ; Gopisetty, Gopal ; Gordian, Edna ; Navarro, Loida ; Hader, Christiane ; Reis, Isildinha ; Schulz, Wolfgang A. ; Singal, Rakesh. / Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target. In: Cancer Research. 2009 ; Vol. 69, No. 4. pp. 1527-1535.
@article{659cfef68d344c89bda70e576f7f1f43,
title = "Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target",
abstract = "Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45α) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45α in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45α in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45α expression in these cells. The 5' 4 CpG region was also frequently methylated in prostate cancer tissues. Meth-ylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2 -) led to a significantly increased expression of GADD45α (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45α in Du145 cells by recombinant expression of GADD45α or pretreatment with 5-azacytidine. Our results show that GADD45α is epigenetically repressed and is a potential target for treatment of prostate cancer. [Cancer Res 2009;69(4):1527-35]",
author = "Kavitha Ramachandran and Gopal Gopisetty and Edna Gordian and Loida Navarro and Christiane Hader and Isildinha Reis and Schulz, {Wolfgang A.} and Rakesh Singal",
year = "2009",
month = "2",
day = "15",
doi = "10.1158/0008-5472.CAN-08-3609",
language = "English",
volume = "69",
pages = "1527--1535",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "4",

}

TY - JOUR

T1 - Methylation-mediated repression of GADD45α in prostate cancer and its role as a potential therapeutic target

AU - Ramachandran, Kavitha

AU - Gopisetty, Gopal

AU - Gordian, Edna

AU - Navarro, Loida

AU - Hader, Christiane

AU - Reis, Isildinha

AU - Schulz, Wolfgang A.

AU - Singal, Rakesh

PY - 2009/2/15

Y1 - 2009/2/15

N2 - Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45α) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45α in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45α in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45α expression in these cells. The 5' 4 CpG region was also frequently methylated in prostate cancer tissues. Meth-ylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2 -) led to a significantly increased expression of GADD45α (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45α in Du145 cells by recombinant expression of GADD45α or pretreatment with 5-azacytidine. Our results show that GADD45α is epigenetically repressed and is a potential target for treatment of prostate cancer. [Cancer Res 2009;69(4):1527-35]

AB - Defects in apoptotic pathway contribute to uncontrolled proliferation of cancer cells and confer resistance to chemotherapy. Growth arrest and DNA damage inducible, alpha (GADD45α) is up-regulated on docetaxel treatment and may contribute to docetaxel-mediated cytotoxicity. We examined the mechanism of regulation of GADD45α in prostate cancer cells and the effect of its up-regulation on sensitivity to docetaxel chemotherapy. Expression of GADD45α in PC3 cells was higher than that in Du145 and LNCaP cells (17- and 12-fold, respectively; P < 0.05). Although the proximal promoter region was unmethylated in all three cell lines, methylation of a 4 CpG region upstream of the proximal promoter correlated inversely with gene expression levels. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyltransferase inhibitors, leading to reactivation of GADD45α expression in these cells. The 5' 4 CpG region was also frequently methylated in prostate cancer tissues. Meth-ylation of this region correlated inversely with gene expression in prostate cancer and benign prostate tissues. The methyl binding protein MeCP2 was associated with the methylated 4 CpGs in Du145 cells, and knockdown of MeCP2 in these cells (Du145 MeCP2 -) led to a significantly increased expression of GADD45α (3-fold; P = 0.035) without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by up-regulation of GADD45α in Du145 cells by recombinant expression of GADD45α or pretreatment with 5-azacytidine. Our results show that GADD45α is epigenetically repressed and is a potential target for treatment of prostate cancer. [Cancer Res 2009;69(4):1527-35]

UR - http://www.scopus.com/inward/record.url?scp=60549108922&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60549108922&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-08-3609

DO - 10.1158/0008-5472.CAN-08-3609

M3 - Article

C2 - 19190346

AN - SCOPUS:60549108922

VL - 69

SP - 1527

EP - 1535

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 4

ER -