Metastasis-associated
protein 1 (MTA1), a component of the
nucleosome-remodeling and
histone deacetylase complex, is widely up-regulated in human
cancers and significantly correlated with
tumor invasion and
metastasis, but the mechanisms involved remain largely unknown. Here, we report that MTA1 transcriptionally represses the expression of RING finger
protein 144A (RNF144A), an uncharacterized gene whose
protein product possesses potential
E3 ubiquitin ligase activity, by recruiting the
histone deacetylase 2 (HDAC2) and
CCAAT/enhancer-binding protein α (c/EBPα)
co-repressor complex onto human RNF144A promoter. Furthermore, an inverse correlation between the expression levels of MTA1 and RNF144A was demonstrated in publicly available
breast cancer microarray datasets and the MCF10
breast cancer progression model system. To address functional aspects of MTA1 regulation of RNF144A, we demonstrate that RNF144A is a novel suppressor of
cancer migration and invasion, two requisite steps of
metastasis in vivo, and knockdown of endogenous RNF144A by small interfering RNAs accelerates the migration and invasion of MTA1-overexpressing cells. These results suggest that RNF144A is partially responsible for MTA1-mediated migration and invasion and that MTA1 overexpression in highly metastatic
cancer cells drives cell migration and invasion by, at least in part, interfering with the suppressive function of RNF144A through transcriptional repression of RNF144A expression. Together, these findings provide novel mechanistic insights into regulation of
tumor progression and
metastasis by MTA1 and highlight a previously unrecognized role of RNF144A in MTA1-driven
cancer cell migration and invasion.