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The Putative Tumor Suppressor microRNA-101 Modulates the Cancer Epigenome by Repressing the Polycomb Group Protein EZH2

¹ Department of Urology, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, and ² Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California

Requests for reprints: Peter A. Jones, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, California 90033. Phone: 323-865-0816; Fax: 323-865-0102; E-mail: jones_p{at}ccnt.usc.edu and Gangning Liang, University of Southern California/Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, NOR7346, Los Angeles, CA 90033. Phone: 323-865-0470; Fax: 323-865-0102; E-mail: gliang{at}usc.edu.

Key Words: cancer • epigenetics • microRNA • Polycomb • EZH2

The Polycomb Repressive Complex 2 (PRC2) mediates epigenetic gene silencing by trimethylating histone H3 lysine 27 (H3K27me3) and is known to aberrantly silence tumor suppressor genes in cancer. EZH2, the catalytic subunit of PRC2, enhances tumorigenesis and is commonly overexpressed in several types of cancer. Our microRNA profiling of bladder transitional cell carcinoma (TCC) patient samples revealed that microRNA-101 (miR-101) is down-regulated in TCC, and we showed that miR-101 inhibits cell proliferation and colony formation in TCC cell lines. Furthermore, our results confirm that miR-101 directly represses EZH2 and stable EZH2 knockdowns in TCC cell lines create a similar growth suppressive phenotype. This suggests that abnormal down-regulation of miR-101 could lead to the overexpression of EZH2 frequently seen in cancer. We conclude that miR-101 may be a potent tumor suppressor by altering global chromatin structure through repression of EZH2. [Cancer Res 2009;69(6):2623–9]