This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-1499v1 69/23/9038    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Huang, Y.-W. Articles by Huang, T. H-M. PubMed PubMed Citation Articles by Huang, Y.-W. Articles by Huang, T. H-M.

Epigenetic Repression of microRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer

¹ Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; ² Division of Biostatistics, ³ Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, and ⁴ Department of Surgery, Washington University School of Medicine and Siteman Cancer Center, St. Louis, Missouri; and ⁵ Department of Obstetrics and Gynecology, UT Southwestern Medical Center at Dallas, Dallas, Texas

Requests for reprints: Tim H-M. Huang, Human Cancer Genetics Program, The Ohio State University, 814 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-8277; Fax: 614-292-5995; E-mail: tim.huang{at}osumc.edu.

Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high mobility group box family, was found to be overexpressed (P < 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P < 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P < 0.001) and poor overall survival (P < 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells. [Cancer Res 2009;69(23):9038–46]

Key Words: DNA methylation • epigenetics • miR-129-2 • SOX4