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1 Confers a Migratory and Invasive Phenotype
Metastasis associated protein 1 (MTA1) belongs to a newly added group of ubiquitously expressed chromatin modifiers named Metastasis Associated Protein (MTA) family, which play an integral role in the Nucleosome Remodeling and histone Deacetylation (NuRD) complexes. Studies revealed that MTA1 is widely up-regulated in a variety of human cancers, including head and neck, lung, breast, liver, gastrointestinal, pancreatic, ovarian, prostate cancers, melanoma, and lymphomas, and the expression levels of MTA1 correlate closely with tumor invasion and metastasis as well as a poor prognosis of cancer patients. The oncogenic property of MTA1 protein is designated as a dual coregulator where the functional status of this protein may vary from a corepressor to a coactivator. Even though the target genes regulated by MTA1 are emerging day by day, the height of research currently demands the lucid role of MTA1 in tumor aggressiveness. In an attempt to identify novel gene targets and functions of MTA1, we have recently worked out that MTA1 may modulate RNF144A (RING finger protein 144A) an uncharacterized gene whose protein product has potential E3 ubiquitin ligase activity.
The MTA1-RNF144A axis came into light with an inverse correlation of the transcript levels between MTA1 and RNF144A in multiple microarray datasets, indicating a potential role of MTA1 in regulation of RNF144A. Foundation stone was further laid via western blot analysis which portrayed a reverse correlation of MTA1 and RNF144A in overexpressed or knock down human breast cancer cell line, cancer tissues and a tumor progression model system, highlighting a potential role of MTA1-RNF144A pathway in tumorigenesis and tumor progression. Functioning as a coregulator, next lead with MTA1 was at transcriptional level where Chromatin ImmunoPrecipitation (ChIP) clearly depicted that MTA1 is recruited onto human RNF144A promoter and inhibits its promoter activity, which came to be evident with luciferase assay later. Now it is in limelight that MTA1 represses RNF144A gene transcription by recruiting the MTA1/ HDAC2 (Histone Deacetylase 2) / c/EBPa (CCAAT/enhancer binding protein alpha) co-repressor complex onto its promoter. Even though the regulation of RNF144A by MTA1 was delineated, the importance of RNF144A in cancer cell migration and invasion remained unclear. From the invasion assay and wound healing assay it was demonstrated that depletion of endogenous RNF144A using RNAi method confers a more migratory and invasive phenotype of cancer cells overexpressing MTA1. These results highlight the contribution of dysregulated MTA1-RNF144A axis in MTA1-driven cancer cell migration and invasion, and thus, targeting this axis may be a promising approach for cancer therapy (Marzook, H., Li, D.Q., Pillai, M.R., Kumar, R. et al, 2012, J.Biol.Chem. 287, 5615-5626). |
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RGCB