Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

• Published in: The Journal of biological chemistry Vol. 287; no. 33; pp. 27843 - 27850
• Main Authors: Reddy, Sirigiri Divijendra Natha, Pakala, Suresh B., Molli, Poonam R., Sahni, Neil, Karanam, Narasimha Kumar, Mudvari, Prakriti, Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.08.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Akt; Animals; Breast Cancer; Cell Survival; Chromatin Immunoprecipitation (ChIP); Chromatin Regulation; Gene Expression Regulation, Enzymologic - physiology; Gene Regulation; HeLa Cells; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Mice; MTA1; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Promoter Regions, Genetic - physiology; PTEN; PTEN Phosphohydrolase - biosynthesis; PTEN Phosphohydrolase - genetics; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - physiology; Trans-Activators; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic - physiology; Up-Regulation - physiology; YY1 Transcription Factor - genetics; YY1 Transcription Factor - metabolism; Gene Regulation; MTA1; Cell Survival; PTEN; Akt; Breast Cancer; Chromatin Immunoprecipitation (ChIP); Chromatin Regulation
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M112.348474

Metastasis-associated protein 1 (MTA1) is widely overexpressed in human cancers and is associated with malignant phenotypic changes contributing to morbidity in the associated diseases. Here we discovered for the first time that MTA1, a master chromatin modifier, transcriptionally represses the expression of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, by recruiting class II histone deacetylase 4 (HDAC4) along with the transcription factor Yin-Yang 1 (YY1) onto the PTEN promoter. We also found evidence of an inverse correlation between the expression levels of MTA1 and PTEN in physiologically relevant breast cancer microarray datasets. We found that MTA1 up-regulation leads to a decreased expression of PTEN protein and stimulation of PI3K as well as phosphorylation of its signaling targets. Accordingly, selective down-regulation of MTA1 in breast cancer cells increases PTEN expression and inhibits stimulation of the PI3K/AKT signaling. Collectively, these findings provide a mechanistic role for MTA1 in transcriptional repression of PTEN, leading to modulation of the resulting signaling pathways. Background: MTA1 is overexpressed in several advanced cancers, but its role in cell survival signaling is yet to be elucidated. Results: MTA1 transcriptionally represses the expression of PTEN and, consequently, PTEN-dependent signaling and functions. Conclusion: PTEN is a target of the MTA1/HDAC4-containing NuRD complex. Significance: This study provides a novel mechanistic insight into the regulation of PTEN by MTA1.