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Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res 2009 Dec 01;69(23):9038-46

Date

11/06/2009

Pubmed ID

19887623

Pubmed Central ID

PMC2789184

DOI

10.1158/0008-5472.CAN-09-1499

Scopus ID

2-s2.0-71549121035   234 Citations

Abstract

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.

Author List

Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, Goodfellow PJ, Miller DS, Huang TH

Author

Yi-Wen Huang PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Base Sequence
Carcinoma, Endometrioid
CpG Islands
DNA Methylation
Endometrial Neoplasms
Female
Gene Expression Regulation, Neoplastic
Gene Silencing
Humans
MicroRNAs
Microsatellite Instability
Molecular Sequence Data
MutL Protein Homolog 1
Nuclear Proteins
SOXC Transcription Factors
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2