Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer
Effects of histone deacetylase inhibitor FR901228 on the expression level of telomerase reverse transcriptase in oral cancer
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DOI：
10.1007/s00280-004-0976-x
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发表时间：
2005-07-01
影响因子：
3
通讯作者：
Kishi, K
中科院分区：
文献类型：
--
作者：
Murakami, J;Asaumi, J;Kishi, K
我们推测是否端粒酶逆转录酶（hTERT）的表达水平将调节剂靶向表观遗传学在口腔癌细胞系。尽管已知hTERT被表观遗传学改变靶向，但仍不清楚靶向表观遗传学的化学剂如何作用于hTERT转录。在本研究中，组蛋白去乙酰化酶（HDAC）抑制剂FR 901228对口腔癌细胞系hTERT转录的表观遗传效应进行了分析，通过RT-PCR。FR 901228可上调hTERT阴性的Hep 2细胞中hTERT mRNA的表达，甚至SAS和KB细胞也表达高水平的hTERT。此外，蛋白质合成抑制剂放线菌酮（CHX）的共处理导致的诱导hTERT转录的FR 901228。这表明FR 901228对hTERT的诱导在一定程度上需要从头蛋白质合成，并且更可能是对表观遗传变化（如组蛋白乙酰化/脱乙酰化）的直接影响而不是间接影响。我们进一步研究了FR 901228对c-myc蛋白的影响，c-myc蛋白是hTERT的主要转录激活因子之一。FR 901228仅在不存在CHX的情况下抑制c-myc蛋白，并且依赖于从头蛋白合成的增强。我们的研究结果表明，c-myc蛋白被FR 901228间接抑制，但可能不会有助于FR 901228诱导的hTERT转录。目前的研究表明，HDAC抑制剂FR 901228诱导hTERT基因的复杂机制，涉及转录因子以外的c-myc，除了抑制组蛋白脱乙酰化。
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.