Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion.
Histone deacetylase (HDAC) inhibitors are known to exert antimetastatic and antiangiogenic activity in vitro and in vivo. RECK is a membrane-anchored glycoprotein that negatively regulates matrix metalloproteinases (MMPs) and inhibits tumor metastasis and angiogenesis. In this study, we test the possibility that HDAC inhibitor may increase RECK expression to inhibit MMP activation and cancer cell invasion. Our results showed that trichostatin A (TSA) up-regulated RECK via transcriptional activation in CL-1 human lung cancer cells. Flow cytometric analysis demonstrated that RECK protein on cell surface was increased after treatment of TSA. Moreover, up-regulation of RECK expression by TSA attenuated MMP-2 activity. To explore whether HDAC inhibitor-induced inhibition of MMP-2 activation is indeed mediated via RECK, we used small interference RNA (siRNA) to block RECK expression and found that inhibition of RECK by siRNA abolished the inhibitory effect of TSA on MMP-2 activation. In addition, TSA suppressed the invasive ability of CL-1 cells. Taken together, this study reveals a novel mechanism by which HDAC inhibitors suppress tumor invasion and provides a new strategy for cancer therapy.
Liu
Li-Teh
LT
Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chang
Hui-Chiu
HC
Chiang
Lien-Chai
LC
Hung
Wen-Chun
WC
D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C115460:RECK protein, human; D034741:RNA, Small Interfering; C012589:trichostatin A; D020778:Matrix Metalloproteinase 2; D006655:Histone Deacetylases