title: Histone deacetylase inhibitor AR42 regulates telomerase activity in human glioma cells via an Akt-dependent mechanism.
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.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ya-Luen
authors.initials: YL
authors.lastname: Yang
authors.forename: Po-Hsien
authors.initials: PH
authors.lastname: Huang
authors.forename: Hao-Chieh
authors.initials: HC
authors.lastname: Chiu
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
authors.forename: Cheng-Ju
authors.initials: CJ
authors.lastname: Kuo
authors.forename: Huan-Da
authors.initials: HD
authors.lastname: Chen
authors.forename: Chang-Shi
authors.initials: CS
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010654:Phenylbutyrates / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D002867:Chromones; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D010654:Phenylbutyrates; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019098:Telomerase; C529674:OSU-HDAC42 compound; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C509186:TERT protein, human; C494929:PTEN protein, human