Deciphering the Role of ADAMTS6 in the Epithelial–Mesenchymal Transition of Lung Adenocarcinoma Cells

A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) is an extracellular matrix (ECM) protease that promotes the invasion of lung adenocarcinoma (LUAD) cells. Herein, we investigate its role in epithelial-mesenchymal transition (EMT), a process that drives metastasis and drug resistance in LUAD. Re-analysis of microarray and RNA sequencing data from LUAD cells revealed that during EMT, TGF-β1 increased <i>ADAMTS6</i> expression, presumably through the SMAD pathway, as SMAD2 loss completely blocked this effect. Moreover, <i>ADAMTS6</i> was shown to occupy hub positions within TGF-β1-associated gene networks. Using additional datasets, we found that <i>ADAMTS6</i> expression increased under other EMT-inducing conditions, including IL-1β induction and acquired gefitinib resistance, but decreased upon knockdown of Twist1, a master regulator of EMT. Knockout of <i>ADAMTS6</i> repressed colony formation, migration, invasion, and doxorubicin resistance but enhanced cell-ECM adhesion in A549 cells. This effect was mediated by EMT inhibition, evidenced by upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and Twist1, and was accompanied by suppressed nuclear translocation of the NF-κB p65 subunit. Re-analysis of transcriptomic data from patient tumors demonstrated that high <i>ADAMTS6</i> expression correlated with the expression of EMT markers, further supporting the <i>ADAMTS6</i>-EMT link. Moreover, high <i>ADAMTS6</i> expression was associated with worse survival prognosis. Overall, <i>ADAMTS6</i> promotes EMT in LUAD cells and may be considered a marker of this process, as well as a potential therapeutic target for its inhibition.