Crosstalk between YAP and TGF beta regulates SERPINE1 expression in mesenchymal lung cancer cells

Abstract

Serpin family E member 1 (SERPINE1), a serine proteinase inhibitor, serves as an important regulator of extra-cellular matrix remodeling. Emerging evidence suggests that SERPINE1 has diverse roles in cancer and is associated with poor prognosis. However, the mechanism via which SERPINE1 is induced in cancer has not been fully determined. In order to examine the molecular mechanism of SERPINE1 expression, the present study took advantage of the isogenic pair of lung cancer cells with epithelial or mesenchymal features. Using genetic perturbation and following biochemical analysis, the present study demonstrated that SERPINE1 expression was upregulated in mesenchymal lung cancer cells and promoted cellular invasiveness. Yes-associated protein (YAP)-dependent SERPINE1 expression was modulated by treatment with a Rho-associated protein kinase inhibitor, Y27632. Moreover, TGF beta treatment supported YAP-dependent SERPINE1 expression, and an enhanced TGF beta response in mesenchymal lung cancer cells promoted SERPINE1 expression. TGF beta-mediated SERPINE1 expression was significantly attenuated by knockdown of YAP or transcriptional co-activator with PDZ-binding motif, suggesting that crosstalk between the TGF beta and YAP pathways underlies SERPINE1 expression in mesenchymal cancer cells.