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DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of <i>DUSP6</i>. In agreement with these data, here we show that <i>DUSP6</i> plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in epithelial to mesenchymal transition (EMT) in NSCLC-<i>DUSP6</i> depleted cells. Data obtained in RNA-seq studies carried out in <i>DUSP6</i> depleted cells identified EGFR, TGF-&#946; and WNT signaling pathways and several genes such as <i>VAV3, RUNXR2, LEF1, FGFR2</i> whose expression is upregulated in these cells and therefore affecting cellular functions such as integrin mediated cell adhesion, focal adhesion and motility. Furthermore, EGF signaling pathway is activated via ERK5 and not ERK1/2 and TGF-&#946; via SMAD2/3 in <i>DUSP6</i> depleted cells. In summary <i>DUSP6</i> is a tumor suppressor in NSCLC and re-establishment of its expression may be a potential strategy to revert poor outcome in NSCLC patients.