High mobility group Box-1 inhibits cancer cell motility and metastasis by suppressing activation of transcription factor CREB and nWASP expression

Abstract

// Zhenghong Zuo 1,2,* , Xun Che 1,* , Yulei Wang 1 , Bowen Li 2 , Jingxia Li 1 , Wei Dai 1 , Charles P. Lin 3 and Chuanshu Huang 1 1 Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China 3 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD, USA * These authors contributed equally to this work Correspondence: Chuanshu Huang, email: // Keywords : HMGB1; metastasis; CREB; nWASP Received : March 27, 2014 Accepted : June 29, 2014 Published : June 30, 2014 Abstract The ability to metastasize is a hallmark of malignant tumors, and metastasis is the principal cause of death of cancer patients. The High Mobility Group Box-1 (HMGB1) is a multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Our current study demonstrated a novel mechanism of HMGB1 in the regulation of cancer cell actin polymerization, cell skeleton formation, cancer cell motility and metastasis. We found that knockdown of HMGB1 in human lung cancer A549 cells significantly increased cell β-actin polymerization, cell skeleton formation, cancer cell migration and invasion in vitro , as well as metastasis in vivo . And this increase could be inhibited by treatment of HMGB1 knockdown cells with recombinant human HMGB1. Further studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit. This reduces nWASP mRNA transcription and expression, further impairing cancer cell motility. Our findings on the novel mechanism underlying the HMGB1 anti-metastatic effect on cancer provides significant insight into the understanding of the nature of HMGB1 in cancer invasion and metastasis, further serving as key information for utilization of HMGB1 and its regulated downstream components as new targets for cancer therapy.