The epigenetic effects of trichostatin A-induced chromatin histone hyperacetylation on hepatocellular carcinoma cell migration

• Main Authors: Kuen-Tyng Lin, 林坤廷
• Other Authors: Yuh-Shan Jou
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/99561964352796142349

博士 === 國防醫學院 === 生命科學研究所 === 93 === Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, has been known to block cellular growth, induce apoptosis and inhibit cell migration in human cancer cell lines. In human hepatocellular carcinoma (HCC) cell lines, the effects of TSA treatment on cell migration are still unknown. In order to investigate the roles of epigenetic modulations, especially histone acetylation, on cancer genes participated in HCC metastasis, HCC cell lines were treated with different concentrations of TSA and in vitro migration activity was measured by using the transwell migration assay. The results indicated that the cell migration activity can be substantially enhanced by TSA treatment in a dose-dependent manner for HCC cell lines Huh7, PLC5 and Hep3B. By RT-PCR and Western blot analysis, the TSA induction on two migration-related gene families, matrix metalloproteinases (MMPs) and integrins, was first examined for revealing the molecular pathways in the enhancement of Hep3B cell migration. The results indicated that the enhancement of Hep3B cell migration was associated with up-regulation of several MMPs and integrin subunits including MMP-1, -2, -9, -10, -13 and integrin subunits of a4, b2, b6 in both mRNA and protein levels. Addition of specific inhibitors or neutralizing antibodies to those MMPs or integrins blocked the TSA-induced cell migration activity in the Hep3B cells. Up-regulated MMP-1, -2 and -9 were also clinicopathologically associated with HCC tumorigenesis (P<0.05) by quantitative RT-PCR analysis. In conclusion, the results suggest that TSA has a novel effect on enhancing migration activities and that histone acetylation plays an important role in HCC cell migration. With further evidence of epigenetic modulation in HCC tissues, TSA treatment or its revealed target pathways will add to the understanding of molecular mechanisms of HCC metastasis and treatment.