Molecular mechanisms in trichostatin A- or sirtinol-inhibited HT29 human colon adenocarcinoma cells proliferation

• Main Authors: De-Shin Yang, 楊德鑫
• Other Authors: 許銘仁
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/86835506390254967153

碩士 === 臺北醫學大學 === 醫學科學研究所 === 98 === Survivin, an inhibitor of apoptosis family member and histone deacetylases (HDACs), are often found over-expressed in human cancers including colorectal cancer and have been implicated in the development and progression of tumorigenesis. Inhibition of HDACs was demonstrated to induce different phenotypes in various transformed cells, including growth arrest, activating apoptotic pathways, mitotic cell death and senescence. However, the mechanisms underlying HDAC inhibition-induced cell death or cell cycle arrest in HT29 human colon adenocarcinoma cells remain to be fully elucidated. We demonstrated in this study that trichostatin A (TSA) or sirtinol, two structurally and functionally different HDAC inhibitors, decreased cell viability and suppressed cell proliferation in HT29 cells. Bax, a pro-apoptotic protein, and p21Cip/Waf1, a cell-cycle regulator, both are elevated in cells exposure to TSA or sirtinol. TSA and sirtinol was shown to suppress transcription factor specific protein 1 (Sp1) activity leading to survivin down-regulation. TSA or sirtinol caused IKK dephosphorylation in a time-dependent manner. In addition, TSA or sirtinol were shown to activate p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). Inhibitors of p38MAPK and AMPK abrogated the TSA- or sirtinol-decreased cell viability suggesting functional crosstalk. Transfection of cells with HDAC3 or HDAC4 increased cell viability further supported the role of HDACs in promoting cell survival. These results suggest that HDAC inhibition may activate p38MAPK or AMPK signaling cascade resulting in HT29 cell dysfunction via regulated Sp1 transcription and down regulating of survivin.