Crosstalk between YAP and TGFβ 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 extracellular 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, TGFβ treatment supported YAP-dependent SERPINE1 expression, and an enhanced TGFβ response in mesenchymal lung cancer cells promoted SERPINE1 expression. TGFβ-mediated SERPINE1 expression was significantly attenuated by knockdown of YAP or transcriptional co-activator with PDZ-binding motif, suggesting that crosstalk between the TGFβ and YAP pathways underlies SERPINE1 expression in mesenchymal cancer cells.

Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

“…In vitro modeling confirmed that TAZ is necessary for TGF-β1-mediated fibrogenesis and vector-driven TAZ synthesis mimics aspects of the TGF-β1-induced phenotype including G 2 /M arrest and acquisition of a profibrotic program [ 27 ]. TAZ is required for maximal TGF-β1-mediated expression of the SMAD target gene encoding plasminogen activator inhibitor-1 (PAI-1), a potent profibrotic clade E member of the serine protease inhibitor family (SERPINE1) [ 27 , 28 , 29 , 30 ], and a similar involvement of YAP in TGF-β1-induced PAI-1 expression is evident in lung tumor cells [ 31 ]. KEGG analysis confirmed, moreover, that convergence of the TGF-β and Hippo signaling pathways regulates transcription of the fibrosis-inducing connective tissue growth factor (CTGF; CCN2) and SERPINE1 genes [ 32 ] ( Figure 1 ).…”

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

“…Exposure of HK2 cells to hypoxic stress similarly promotes G 2 /M stalling and PAI-1 induction while TAZ overexpression leads to the accumulation of HK-2 cells in G 2 /M phase. TAZ is, in fact, required for maximal TGF-β1-mediated PAI-1 synthesis in proximal tubular cells (Liu et al, 2015;Samarakoon et al, 2015;Anorga et al, 2018;Bessho et al, 2019) and a similar involvement of YAP in TGF-β1induced PAI-1 expression is evident in lung tumor cells (Kong et al, 2021). KEGG analysis confirmed that convergence of the TGF-β and Hippo signaling pathways regulates transcription of the profibrotic CCN2 and SERPINE1 genes (Figure 7).…”

Modeling of Aryl Hydrocarbon Receptor Pathway Intrinsic Immunometabolic Role using Glioblastoma Stem Cells and Patient-Derived Organoids

“…Importantly, we determined that ten of the 41 genes were downregulated following AHR inhibition in GBMO-30 and significantly associated with survival supporting a role of inactivation of AHR on potential genes that drive mortality in GBM. These include PLP2 , a gene involved in autophagy and ER stress in GBM 32 ; SGMS2, which is associated with aggressive breast cancer 33 ; MT1H, which is a tumor suppressor in liver cancer 34 ; and SERPINE1 , which is associated with several cancers 35 ( Fig. 7b- e ).…”