Type II transglutaminase stimulates epidermal cancer stem cell epithelial-mesenchymal transition

// Matthew L. Fisher 1 , Gautam Adhikary 1 , Wen Xu 1 , Candace Kerr 1 , Jeffrey W. Keillor 5 , Richard L. Eckert 1, 2, 3, 4 1 Departments of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA 2 Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA 3 Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA 4 Marlene and Stewart Greenebaum Cancer, University of Maryland School of Medicine, Baltimore, Maryland, USA 5 Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada Correspondence to: Richard L. Eckert, e-mail: reckert@umaryland.edu Keywords: epidermal squamous cell carcinoma, type II transglutaminase, cancer stem cell, TG2, epithelial mesenchymal transition Received: January 23, 2015 Accepted: April 25, 2015 Published: May 08, 2015 ABSTRACT Type II transglutaminase (TG2) is a multifunctional protein that has recently been implicated as having a role in ECS cell survival. In the present study we investigate the role of TG2 in regulating epithelial mesenchymal transition (EMT) in ECS cells. Our studies show that TG2 knockdown or treatment with TG2 inhibitor, results in a reduced EMT marker expression, and reduced cell migration and invasion. TG2 has several activities, but the most prominent are its transamidase and GTP binding activity. Analysis of a series of TG2 mutants reveals that TG2 GTP binding activity, but not the transamidase activity, is required for expression of EMT markers (Twist, Snail, Slug, vimentin, fibronectin, N-cadherin and HIF-1α), and increased ECS cell invasion and migration. This coupled with reduced expression of E-cadherin. Additional studies indicate that NFϰB signaling, which has been implicated as mediating TG2 impact on EMT in breast cancer cells, is not involved in TG2 regulation of EMT in skin cancer. These studies suggest that TG2 is required for maintenance of ECS cell EMT, invasion and migration, and suggests that inhibiting TG2 GTP binding/G-protein related activity may reduce skin cancer tumor survival.