miR-200a Regulates SIRT1 Expression and Epithelial to Mesenchymal Transition (EMT)-like Transformation in Mammary Epithelial Cells

• Published in: The Journal of biological chemistry 2011-07, Vol.286 (29), p.25992-26002
• Main Authors: Eades, Gabriel, Yao, Yuan, Yang, Muhua, Zhang, Yongshu, Chumsri, Saranya, Zhou, Qun
• Format: Article
• Language: English
• Subjects: Antigens, CD; Base Sequence; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cadherins - genetics; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; DNA Methylation - drug effects; DNA Methylation - genetics; Epigenetics; Epithelial Cell; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Feedback, Physiological - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Regulation; Gene Silencing; HEK293 Cells; Humans; Mammary Glands, Human - cytology; Mammary Glands, Human - drug effects; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; MicroRNA; MicroRNAs - genetics; Promoter Regions, Genetic - genetics; SIRT; Sirtuin 1 - genetics; Transformation; Transforming Growth Factor beta - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.229401

Evidence supports a critical role for microRNAs (miRNAs) in regulation of tissue-specific differentiation and development. Signifying a disruption of these programs, expression profiling has revealed extensive miRNA dysregulation in tumors compared with healthy tissue. The miR-200 family has been established as a key regulator of epithelial phenotype and, as such, is deeply involved in epithelial to mesenchymal transition (EMT) processes in breast cancer. However, the effects of the miR-200 family on transformation of normal mammary epithelial cells have yet to be fully characterized. By examining a TGF-β driven model of transformation of normal mammary epithelium, we demonstrate that the class III histone deacetylase silent information regulator 1 (SIRT1), a proposed oncogene in breast cancer, is overexpressed upon EMT-like transformation and that epigenetic silencing of miR-200a contributes at least in part to the overexpression of SIRT1. We have established the SIRT1 transcript as subject to regulation by miR-200a, through miR-200a targeting of SIRT1 3′-UTR. We also observed SIRT1 and miR-200a participation in a negative feedback regulatory loop. Restoration of miR-200a or the knockdown of SIRT1 prevented transformation of normal mammary epithelial cells evidenced by decreased anchorage-independent growth and decreased cell migration. Finally, we observed SIRT1 overexpression in association with decreased miR-200a in breast cancer patient samples. These observations provide further evidence for a critical tumor suppressive role of the miR-200 family in breast epithelium in addition to identifying a novel regulatory mechanism, which may contribute to SIRT1 up-regulation in breast cancer.