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 histone deacetylase (HDAC) inhibitor FR901228 on hTERT transcription were analysed by RT-PCR in oral cancer cell lines. The mRNA expression of hTERT was upregulated after exposure to FR901228 in hTERT-negative Hep2 cells, even in the hTERT highly expressed SAS and KB cells.Moreover, co-treatment 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, dependent of the enhancement of de novo protein synthesis. Our results indicate that c-myc protein is repressed indirectly by FR901228 but may not contribute FR901228-induced hTERT transcription. The present study showed that the HDAC inhibitor FR901228 induced the hTERT gene by a complex mechanism that involved other transcription factors except for c-myc, in addition to the inhibition of histone deacetylation.

Oral Cancer Diagnosis via a Ferrocenylnaphthalene Diimide–Based Electrochemical Telomerase Assay

“…1), indicating that telomerase was indeed present in the cells. This result is consistent with previously reported results for SAS, HSC-2, and HSC-3 cells (8,9 ). Nonetheless, telomerase activity varied considerably among the 4 types of cells.…”

“…Because telomerase activity is observed in many tumor cells (1,2,3,8,9 ), human oral squamous carcinoma cell lines SAS, Ca9 -22, HSC-2, and HSC-3 were tested first for telomerase. Cells from each of these lines were solubilized with the lysis buffer to yield variable amounts of protein.…”

Tumor Microenvironment may Shape the Function and Phenotype of NK Cells Through the Induction of Split Anergy and Generation of Regulatory NK Cells

“…Indeed, blocking NF-jB in oral tumors was found to increase CD44 surface receptor expression, which is one of the hallmarks of stem cells (unpublished results). In addition, blocking of NF-jB nuclear function in a primary Oral tumor OSCCs and in a non-tumorigenic oral cells (HOK-16B) as well as in an established tumor line, HEp-2 cells known to be Hela contaminant (Jewett et al 2003;Murakami et al 2004Murakami et al , 2005Abdulkarim et al 2002), augmented cytotoxicity and the release of key cytokines such as IFN-c from the NK cells (Jewett et al 2003(Jewett et al , 2006. Similarly, inhibition of NF-jB by Sulindac increased the functional activation of NK cells and enhanced anti-tumor cytotoxic activity (Jewett et al 2003(Jewett et al , 2006.…”

Human telomerase inhibitors from microbial source

“…It has got a role in c-MYC expression regulation whose repression has been implicated in several apoptosis pathways (Wang et al 1998). The decrease in c-MYC will ultimately down regulate hTERT expression (Murakami et al 2005). However, precise mechanism between hTERT and c-myc expressions remains to be uncovered.…”