Inhibition of histone deacetylase attenuates hypoxia-induced migration and invasion of cancer cells via the restoration of RECK expression.
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 RECK expression and used HDAC inhibitor (HDACI) inhibition to restore RECK expression to inhibit cancer cell migration and invasion. HDACIs, including trichostatin A (TSA), completely rescued RECK 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 RECK downregulation and inhibited the migration and invasion of cancer cells. In conclusion, the inhibition of HDAC successfully restored the expression of RECK under hypoxic conditions. This resulted in the inhibition of cancer cell migration and invasion through the repression of MMP-2 and MMP-9 activity.
Jeon
Hye Won
HW
School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu, Korea.
Lee
You Mie
YM
D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; C115460:RECK protein, human; D034741:RNA, Small Interfering; C012589:trichostatin A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D056284:Histone Deacetylase 1