Transglutaminase 2 (TG2) is a highly complex protein with enzymatic and non-enzymatic functions. It is localized in multiple cellular compartments, inside and outside the cell. Overexpression of TG2 has been implicated in cancer development. However, relatively little attention has been paid to the effects of extracellular TG2. Here, we examined the involvement of extracellular TG2 in cell migration using a lung cancer cell line CL1-0 and its invasive subline CL1-5. Our results showed that CL1-5 exhibits higher levels of TG2 in cell lysates and conditioned medium, when compared with CL1-0. Exogenous application of recombinant TG2 protein to CL1-0 cells substantially augmented migration. Inclusion of TG2 antibody to block extracellular TG2 hampered migration of CL1-5 cells. The stimulatory effect of extracellular TG2 on cell migration was independent of its transamidase activity, as treatment of cells with the TG2 inhibitor Z-DON did not suppress migration. Further examination of the regulatory mechanisms for TG2 expression revealed that the DNA demethylating agent 5-Aza-2'-deoxycystidine increases levels of TG2, but the histone deacetylase inhibitor trichostatin A exerts no effect on CL1- 0 cells. Collectively, our results demonstrated the significance of extracellular TG2 in promoting migration of lung cancer cells. Blockade of extracellular TG2 could be a potential strategy for cancer therapy.
