Suppression of lung cancer cell invasion and metastasis by connexin43 involves the secretion of follistatin-like 1 mediated via histone acetylation.

Although connexin has been recognized as a tumor suppressor in many types of cancer, the underlying mechanisms are poorly understood. We have previously shown that transfection of connexin43 (Cx43) cDNA retarded the growth of a highly metastatic human pulmonary giant cell carcinoma cell line, PG, both in vitro and in vivo. Here, we further demonstrate that the metastasis and invasion, but not the migration, of PG cells are also inhibited following Cx43 transfection. The diminishment of metastasis and invasion is associated with down-regulation of genes including MMP-2, S100A, LAMA4, and HDAC10, as well as up-regulation of genes such as MTSS1 and FSTL1 as revealed by gene chip analysis. Interestingly, the suppression effects of Cx43 are related to secreted factor(s), which are blocked by FSTL1 antibody treatment in a dose-dependent manner. Furthermore, the FSTL1 promoter was shown to be associated with acetylated histones H3 and H4 upon Cx43 transfection. These data suggest that Cx43 inhibits the invasion and metastasis of PG cells by modulating the secretion of FSTL1, which is regulated by histone acetylation. Cx43 may act as a "histone deacetylase inhibitor" to modulate gene expression and subsequent cellular functions in PG cells.