Histone deacetylase inhibitor AR42 regulates telomerase activity in human glioma cells via an Akt-dependent mechanism
Journal
Biochemical and Biophysical Research Communications
Journal Volume
435
Journal Issue
1
Date Issued
2013-05
Author(s)
Abstract
Epigenetic regulation via abnormal activation of histone deacetylases (HDACs) is a mechanism that leads to cancer initiation and promotion. Activation of HDACs results in transcriptional upregulation of human telomerase reverse transcriptase (hTERT) and increases telomerase activity during cellular immortalization and tumorigenesis. However, the effects of HDAC inhibitors on the transcription of hTERT vary in different cancer cells. Here, we studied the effects of a novel HDAC inhibitor, AR42, on telomerase activity in a PTEN-null U87MG glioma cell line. AR42 increased hTERT mRNA in U87MG glioma cells, but suppressed total telomerase activity in a dose-dependent manner. Further analyses suggested that AR42 decreases the phosphorylation of hTERT via an Akt-dependent mechanism. Suppression of Akt phosphorylation and telomerase activity was also observed with PI3K inhibitor LY294002 further supporting the hypothesis that Akt signaling is involved in suppression of AR42-induced inhibition of telomerase activity. Finally, ectopic expression of a constitutive active form of Akt restored telomerase activity in AR42-treated cells. Taken together, our results demonstrate that the novel HDAC inhibitor AR42 can suppress telomerase activity by inhibiting Akt-mediated hTERT phosphorylation, indicating that the PI3K/Akt pathway plays an important role in the regulation of telomerase activity in response to this HDAC inhibitor.
Subjects
Glioma | Histone deacetylase inhibitor | PI3K/Akt pathway | Telomerase reverse transcriptase
Glioma; Histone deacetylase inhibitor; PI3K/Akt pathway; Telomerase reverse transcriptase
SDGs
Other Subjects
2 morpholino 8 phenylchromone; ar 42; histone deacetylase inhibitor; messenger RNA; phosphatidylinositol 3 kinase; protein kinase B; telomerase; unclassified drug; antineoplastic activity; article; concentration response; controlled study; down regulation; enzyme phosphorylation; enzyme regulation; glioma cell; human; human cell; molecular mechanics; priority journal; protein dephosphorylation; signal transduction; upregulation; Cell Line, Tumor; Chromones; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glioma; Histone Deacetylase Inhibitors; Humans; Morpholines; Mutation; Phenylbutyrates; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Telomerase
Type
journal article