The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells.
Activation of telomerase, essential for cellular immortalization and transformation, requires the induction of its catalytic component, telomerase reverse transcriptase (hTERT). However, biochemical and genetic mechanisms for the control of hTERT expression remain undefined. In the present study, we demonstrate that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) induces hyperacetylation of histones at the hTERT proximal promoter, directly transactivates the hTERT gene in normal human telomerase-negative cells, and upregulates hTERT expression in telomerase-positive tumor cells. Overexpression of HDAC1 leads to repression of the hTERT promoter activity. TSA-mediated activation of the hTERT promoter is abolished by the mutation of Sp1 sites at the proximal promoter, suggesting that the effect of TSA is regulated through Sp1 motifs. We also show a physical interaction of Sp1 with HDAC1 and the presence of HDAC1 at the hTERT promoter region. Moreover, hyperacetylation of histones at the hTERT promoter is associated with the natural up-regulation of hTERT expression that occurs in activated T lymphocytes. Taken together, histone acetylation/deacetylation may be a common underlying feature to hTERT transactivation/repression in human normal and malignant cells.
Hou
Mi
M
Department of Medicine, Center for Molecular Medicine, Karolinska Hospital and Institutet, Stockholm, Sweden.
Wang
XiongBiao
X
Popov
Nikita
N
Zhang
Anju
A
Zhao
Xiaoyan
X
Zhou
Rong
R
Zetterberg
Anders
A
Björkholm
Magnus
M
Henriksson
Marie
M
Gruber
Astrid
A
Xu
Dawei
D
D000107:Acetylation / Q000187:drug effects; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D019098:Telomerase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016329:Sp1 Transcription Factor; C012589:trichostatin A; D019098:Telomerase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases