Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells.
Telomerase activity is involved in cellular immortality. We have recently demonstrated that telomerase activity is closely associated with cell proliferation in prostate cancers. Telomerase is composed primarily of the catalytic subunit (hTERT) and the RNA template (hTERC), and hTERT expression is regulated by several factors such as c-MYC and p21(Waf1). Histone deacetylase (HDAC) inhibitors are known to modulate transcription and exhibit antiproliferative effects on cancer cells. The present study was designed to evaluate the effects of HDAC inhibitors on hTERT mRNA expression in prostate cancer cells. LNCaP and PC-3 cells were treated with HDAC inhibitors, trichostatin A (TSA) and sodium butyrate (NaB); mRNA expression and telomerase activity were evaluated by RT-PCR and the TRAP assay, respectively. In LNCaP cells, hTERT mRNA expression was suppressed at 1 and 3 hr after treatment with 1 microM TSA and 4 mM NaB, respectively, followed by inhibition of telomerase activity. The inhibition of hTERT mRNA expression preceded suppression of cell proliferation. In PC-3 cells, TSA and NaB also inhibited cell proliferation, hTERT mRNA expression and telomerase activity. In both cell lines, TSA and NaB had no effect on hTERC expression, or on expression of c-myc and p21(Waf1) mRNA. These effects of TSA and NaB were unlikely to be consequences of cell cycle arrest, apoptosis, or cell differentiation. Thus, HDAC inhibitors down-regulated telomerase activity via suppression of hTERT mRNA expression. Our study identified a novel mechanism for the antiproliferative effects of HDAC inhibitors on prostate cancer cells.
Suenaga
Mitsuhiro
M
First Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
Soda
Hiroshi
H
Oka
Mikio
M
Yamaguchi
Akihiko
A
Nakatomi
Katsumi
K
Shiozawa
Ken
K
Kawabata
Shigeru
S
Kasai
Takashi
T
Yamada
Yasuaki
Y
Kamihira
Shimeru
S
Tei
Chuwa
C
Kohno
Shigeru
S
D002087:Butyrates / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C012589:trichostatin A; D019098:Telomerase; D017430:Prostate-Specific Antigen