Metastasis-associated Protein 1 Drives Tumor Cell Migration and Invasion through Transcriptional Repression of RING Finger Protein 144A

• Published in: The Journal of biological chemistry Vol. 287; no. 8; pp. 5615 - 5627
• Main Authors: Marzook, Hezlin, Li, Da-Qiang, Nair, Vasudha S., Mudvari, Prakriti, Reddy, Sirigiri Divijendra Natha, Pakala, Suresh B., Santhoshkumar, T.R., Pillai, M. Radhakrishna, Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.02.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Carrier Proteins; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell Line, Tumor; Cell Movement - genetics; Computational Biology; Gene Silencing; HeLa Cells; Histone Deacetylase 2 - metabolism; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Invasion; Mice; Migration; Molecular Bases of Disease; MTA1; Neoplasm Invasiveness; Neoplasm Metastasis; Promoter Regions, Genetic - genetics; Repressor Proteins - genetics; Repressor Proteins - metabolism; RING Finger Protein; RNA, Messenger - genetics; RNA, Messenger - metabolism; Trans-Activators; Transcription Regulation; Transcription, Genetic - genetics; Tumor Cell Biology; Tumor Metastases; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Transcription Regulation; Tumor Cell Biology; MTA1; Migration; Tumor Metastases; Invasion; RING Finger Protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.314088

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. The mechanistic role of MTA1 in tumor aggressiveness is yet to be deciphered. RNF144A is a direct target of transcriptional repression by MTA1 and inhibits migration and invasion. Transcriptional repression of RNF144A by MTA1 confers a migratory and invasive phenotype of cancer cells. This study provides novel mechanistic insights into regulation of tumor progression by MTA1.