Data from Inhibition of Histone Deacetylase Attenuates Hypoxia-Induced Migration and Invasion of Cancer Cells via the Restoration of RECK Expression

Abstract

<div>Abstract<p>Hypoxia is a strong signal for cell migration and invasion in cancer. The reversion-inducing cysteine-rich protein with Kazal motif (RECK), a tumor suppressor, inhibits cancer cell migration and invasion and is frequently silenced in aggressive tumor cells by histone deacetylases (HDAC). However, the effect of RECK silencing in several cancer cells in a hypoxic microenvironment has not been fully delineated. In this report, we investigated whether hypoxia suppressed <i>RECK</i> expression and used HDAC inhibitor (HDACI) inhibition to restore <i>RECK</i> expression to inhibit cancer cell migration and invasion. HDACIs, including trichostatin A (TSA), completely rescued <i>RECK</i> expression, which was suppressed by hypoxia, in the H-Ras–transformed human breast MCF10A and the HT1080 cell lines (human fibrosarcoma). TSA suppressed the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9, induced by hypoxia, and significantly inhibited hypoxia-stimulated migration and invasion of both cancer cells. RECK overexpression significantly inhibited the migration and invasion of cancer cells induced by hypoxia. The hypoxic effect on the migration and invasion of cells was equivalent to the effect seen using the small interfering RNA (siRNA) of RECK under normoxia, suggesting an inhibitory role for RECK in hypoxic conditions. We also showed that siRNA silencing of HDAC1 suppressed hypoxia-induced <i>RECK</i> downregulation and inhibited the migration and invasion of cancer cells. In conclusion, the inhibition of HDAC successfully restored the expression of <i>RECK</i> under hypoxic conditions. This resulted in the inhibition of cancer cell migration and invasion through the repression of MMP-2 and MMP-9 activity. Mol Cancer Ther; 9(5); 1361–70. ©2010 AACR.</p></div>