A Mercaptoacetamide-Based Class II Histone Deacetylase Inhibitor Suppresses Cell Migration and Invasion in Monomorphic Malignant Human Glioma Cells by Inhibiting FAK/STAT3 Signaling

Abstract

Histone deacetylase inhibitors (HDACIs) have emerged as potential anticancer agents for the treatment of solid and hematopoietic cancers. Several HDACIs delay cell growth, induce differentiation, or activate apoptosis in multiple types of tumors, including glioblastomas. In the present study, we showed that the mercaptoacetamide-based HDACI W2 inhibits cell migration and invasion in monomorphic malignant human glioma cells. W2 treatment significantly decreased the activity and expression levels of matrix metalloprotease-2 in malignant A172 cells but not in U373MG cells. Key signaling pathways involved in cell migration and invasion, including PI3K-AKT, ERK-JNK-P38, and FAK/STAT3, were examined to identify the mechanism of action of W2. W2 increased the phosphorylation of AKT and altered cell migration and invasion in an AKT-independent manner. W2 inhibited the phosphorylation of FAK/STAT3, and treatment with a FAK/STAT3 inhibitor significantly suppressed cancer cell migration and MMP-2 activity in the presence of W2. In addition, W2 significantly inhibited the nuclear translocation of phospho-STAT3. Taken together, our results suggest that W2 suppresses cancer cell migration and invasion by inhibiting FAK/STAT3 signaling and STAT3 translocation to the nucleus in monomorphic malignant human glioma cells. J. Cell. Biochem. 118: 4672-4685, 2017. (c) 2017 Wiley Periodicals, Inc.