title: Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer.
abstract: We speculated whether or not the expression level of telomerase reverse transcriptase (hTERT) would be modulated by agents targeting epigenetics in oral cancer cell lines. Although hTERT is known to be targeted by epigenetic changes, it remains unclear how chemoagents targeting epigenetics work on hTERT transcription. In the present study, the epigenetic effects of the histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription in oral cancer cell lines were analyzed by RT-PCR. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, and even SAS and KB cells expressed high levels of hTERT. Moreover, cotreatment of protein synthesis inhibitor cycloheximide (CHX) resulted in the induction of hTERT transcription by FR901228. This suggests that the induction of hTERT by FR901228 requires de novo protein synthesis to some extent and is more likely a direct than an indirect effect on epigenetic changes such as histone acetylation/deacetylation. We further examined the effect of FR901228 on c-myc protein, which is one of the main hTERT transcription activators. FR901228 repressed c-myc protein only in the absence of CHX, and depended on the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute to FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved transcription factors other than c-myc, in addition to inhibition of histone deacetylation.
authors.affiliation: Department of Oral and Maxillofacial Radiology, Field of Tumor Biology, Graduate School of Medicine and Dentistry, Okayama University, Shikata-cho, Okayama 700-8525, Japan. jun-m@md.okayama-u.ac.jp
authors.forename: Jun
authors.initials: J
authors.lastname: Murakami
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Asaumi
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawai
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Tsujigiwa
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Yanagi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagatsuka
authors.forename: Tetsuyoshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Susumu
authors.initials: S
authors.lastname: Kokeguchi
authors.forename: Shoji
authors.initials: S
authors.lastname: Kawasaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kuroda
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Nagahide
authors.initials: N
authors.lastname: Matsubara
authors.forename: Kanji
authors.initials: K
authors.lastname: Kishi
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D047630:Depsipeptides / Q000494:pharmacology*; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000096:biosynthesis* / Q000187:drug effects*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; C087123:romidepsin; D019098:Telomerase