Histone deacetylase inhibitors suppress telomerase reverse transcriptase mrna expression in prostate cancer cells

Abstract

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 p21Waf1 . 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 M 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 p21Waf1 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.

Imatinib mesylate (Gleevec) downregulates telomerase activity and inhibits proliferation in telomerase-expressing cell lines

“…For example, hTR antisense inhibited TA in human pancreatic carcinoma cell line, concomitantly with a significant decrease in proliferation, without a crisis or senescence phenomenon Teng and Fahey, 2002). In another study, histone deacetylase inhibitors, which suppress hTERT expression in prostate cancer cells, also inhibited cell proliferation inhibition with no cell cycle arrest, apoptosis or cell differentiation (Suenaga et al, 2002). The results of our study show that IM inhibits proliferation by cell cycle arrest and not by apoptosis.…”

Cell death in irradiated prostate epithelial cells: role of apoptotic and clonogenic cell kill

“…If proven to be important in prostate cancer, the former mechanism of cell death might be augmented in vivo using radiotherapy in conjunction with inhibitors of prostate cancer cell proliferation such as retinoic acid, antisense to cdk inhibitors, inhibitors of telomerase, or inhibitors of histone deactylase (HDAC). 58,59 Indeed these agents are currently being prospectively tested as single agents or in combination with chemotherapy in phase I/II trials; our results suggest further studies of the efficacy of these agents in combination with radiation as a novel prostate treatment strategy are necessary.…”

Antiproliferative effects of the histone deacetylase inhibitor FR901228 on small‐cell lung cancer lines and drug‐resistant sublines

“…10 Furthermore, the SCLC cells used here were deficient in Rb, which is a downstream protein effector of the p21…”

“…9 We have recently reported that the HDAC inhibitors, trichostatin A and sodium butyrate inhibit the expression of the catalytic component of telomerase (hTERT) mRNA and telomerase activity in prostate cancer cells in vitro. 10 Telomerase is a specialized DNA polymerase containing the RNA template (hTERC), the function of which is to maintain the ends of chromosomes. Telomerase reactivation is commonly associated with immortality of cancer cells and is also closely related to their proliferation.…”