Transcriptional activation of estrogen receptor alpha in human breast cancer cells by histone deacetylase inhibition.
Recent findings have established a connection between DNA methylation and transcriptionally inactive chromatin characterized by deacetylated histones. Because the absence of estrogen receptor alpha (ERalpha) gene expression has been associated with aberrant methylation of its CpG island in a significant fraction of breast cancers, we tested whether histone deacetylase activity contributes to the transcriptional inactivation of the methylated ER gene in a panel of ER-negative human breast cancer cells. Treatment of these cells with trichostatin A, a specific histone deacetylase inhibitor, led to dose- and time-dependent re-expression of ER mRNA as detected by reverse transcription-PCR without alteration in ERalpha CpG island methylation. Trichostatin A-induced ER re-expression was associated with increased sensitivity to DNase I at the ER locus in MDA-MB-231 cells. These data implicate inactive chromatin mediated by histone deacetylation as a critical component of ER gene silencing in human breast cancer cells. Therefore, histone deacetylation may be a potential target for therapeutic intervention in the treatment of a subset of ER-negative breast cancers.
Yang
X
X
The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Ferguson
A T
AT
Nass
S J
SJ
Phillips
D L
DL
Butash
K A
KA
Wang
S M
SM
Herman
J G
JG
Davidson
N E
NE
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D003850:Deoxyribonuclease I / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D002843:Chromatin; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D011960:Receptors, Estrogen; C012589:trichostatin A; D003850:Deoxyribonuclease I; D006655:Histone Deacetylases