The Presence of 5-Hmc Is an Epigenetic Feature Promoting Growth in Uterine Fibroids

Presentation Number: SUN-0034
Date of Presentation: June 22nd, 2014

Antonia Navarro*1, Ping Yin2, Diana Monsivais3, Masanori Ono2 and Serdar Ekrem Bulun1
1Northwestern Univ, Chicago, IL, 2Northwestern University, 3Northwestern University, Chicago, IL

Abstract

The Presence of 5-hmC is an Epigenetic Feature Promoting Growth in Uterine Fibroids

Uterine leiomyoma, or fibroids, represent the most common benign tumors of the female reproductive tract. They become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of DNA methylation (5-mC) has been demonstrated at the genome-wide in leiomyoma tissues; however, the role of the newly identified epigenetic mark DNA hydroxymethylation (5-hmC) and its regulators the ten-eleven translocation (TET) proteins remain fully unexplored. In this study we used human uterine leiomyoma and normal myometrial tissues to characterize the role of 5-hmC and TET proteins in leiomyoma. We demonstrated higher 5-hmC levels in leiomyoma tissues than in normal myometrial tissues. In addition, we also observed that the increase in 5-hmC levels is due to the upregulation of TET1 and TET3 mRNA and protein levels in leiomyoma tissues. Functionally, we demonstrated that independent silencing of TET1 and TET3 by siRNA lead to a significant reduction in 5-hmC levels in leiomyoma. Moreover, silencing of TET1 and TET3 interestingly resulted in significant decreased in cell proliferation measured by PCNA levels and BrdU-incorporation. Finally, treatment with the oncometabolite 2-HG, a competitive inhibitor of TET proteins resulted in a significant decreased in 5-hmC, and it also lead to a substantial decrease in cell proliferation in leiomyoma. This study presents the first evidence for an epigenetic imbalance of the 5-hmC homeostasis in uterine leiomyoma due to the increase of 5-hmC through the upregulation of TET1 and TET3 proteins. Our data suggest a possible functional role of 5-hmC in the pathogenesis of this disease, and the identification of 5-hmC and its regulators could be potential diagnostic and therapeutic targets in uterine leiomyoma.

 

Nothing to Disclose: AN, PY, DM, MO, SEB