Trichostatin A and sirtinol suppressed survivin expression through AMPK and p38MAPK in HT29 colon cancer cells

BackgroundElevated levels of survivin and histone deacetylases (HDACs) are often found over-expressed in human cancers, including colorectal cancer, and have been implicated in tumorigenesis. HDAC inhibition induces growth arrest and cell death in various transformed cell; however, the mechanisms by which this reduces cell viability in colorectal cancer cells remain unexplained.MethodsWe explored the actions of two HDAC inhibitors, trichostatin A (TSA) and sirtinol, in HT29 colon cancer cells.ResultsTSA and sirtinol induced apoptosis and inhibited cell proliferation in HT29 cells. These results are associated with the modulation of survivin. Survivin promoter luciferase activity and Sp1, a transcription factor that contributes to survivin expression, were suppressed in cells exposed to TSA or sirtinol. TSA and sirtinol also activated p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). Inhibitors of p38MAPK or AMPK signaling abrogated TSA and sirtinol's effects of decreasing cell viability. Survivin promoter luciferase activity in the presence of TSA or sirtinol was restored by AMPK dominant negative mutant or p38MAPK inhibitor. Furthermore, Sp1 binding to the survivin promoter region decreased while p63 binding to the promoter region increased after TSA or sirtinol exposure.ConclusionsWe report a p38MAPK- and AMPK-mediated downregulation of survivin, and its functional correlation with decreased colon cancer cell viability in the presence of HDAC inhibitor. p63 and Sp1 may also contribute to TSA and sirtinol actions.General significanceThis study delineates, in part, the underlying mechanisms of TSA and sirtinol in decreasing survivin expression and subsequent colon cancer cell viability.

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► TSA and sirtinol suppress survivin expression through activating AMPK and p38MAPK.
► TSA and sirtinol decrease cell viability through activating AMPK and p38MAPK.
► TSA and sirtinol recruit p63 to the survivin promoter region.