Trichostatin A 誘導神經膠瘤細胞死亡的分子機轉探討

Abstract

Histone acetylation is typically associated with increased transcription and is regulated by two opposing classes of enzymes: histone acetyltransferases (HATs), which add acetyl group to histone, and histone deacetylases (HDACs), which catalyze their removal. HDACs have been shown to participate in various physiological responses including cell-cycle progression and differentiation. Many studies demonstrated that several types of cancer cell are characterized by the elevation of HDAC expression. Trichostatin A (TSA), a HDAC inhibitor, was demonstrated to induce cell cycle arrest, promote cell differentiation or apoptosis, and inhibit metastasis in cancer cells. However, the precise mechanism involved in TSA-induced cell death remains unclear. In the present study, TSA was demonstrated to decrease cell viability in C6 glioma cells. TSA also induced cell apoptosis as determined by flowcytometry and DNA laddering. TSA increased p53 reporter activity as determined by reporter assay. Apoptotic protein such as Bax was elevated in C6 cells exposure to TSA. Survivin, a member of inhibitor of apoptosis (IAP) protein, was significantly decreased in TSA-treated C6 cells. In addition to apoptotic proteins, TSA was also shown to decrease IKK phosphorylation and to inhibit NF-?羠 reporter activity. Similar to previous studies, TSA induced p21Cip1/Waf1 expression and decreased cyclin D1 expression. Taken together, TSA may cause cell apoptosis through increasing p53 activity resulting in Bax expression and survivin supression. IKK-NF-?羠 cascade inhibition may also contributed to TSA apoptotic effect. Furthermore, TSA may also affect cell cycle progression through regulating p21Cip1/Waf1 and cyclin D1 expression.