5-hydroxymethylcytosine promotes proliferation of human uterine leiomyoma: A biological link to a new epigenetic modification in benign tumors

Antonia Navarro, Ping Yin, Masanori Ono, Diana Monsivais, Molly B. Moravek, John S.V. Coon, Matthew T. Dyson, Jian Jun Wei, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Context: Uterine leiomyoma, or fibroids, represent the most common benign tumors of the female reproductive tract. A newly discovered epigenetic modification, 5-hydroxymethylation (5-hmC), and its regulators, the TET (Ten Eleven Translocation) enzymes, were implicated in the pathology of malignant tumors; however, their roles in benign tumors, including uterine fibroids, remain unknown.

Objective: To determine the role of 5-hmC and TET proteins in the pathogenesis of leiomyoma using human uterine leiomyoma and normal matched myometrial tissues and primary cells.

Design: 5-hmC levels were determined by ELISA and immunofluorescent staining in matched myometrial and leiomyoma tissues. TET expression was analyzed by quantitative RT-PCR and immunoblotting. TET1 or TET3 were silenced or inhibited by small interferingRNAor 2-hydroxyglutarate to study their effects on 5-hmC content and cell proliferation.

Results: We demonstrated significantly higher 5-hmC levels in the genomic DNA of leiomyoma tissue compared to normal myometrial tissue. The increase in 5-hmC levels was associated with the up-regulation of TET1 or TET3 mRNA and protein expression in leiomyoma tissue. TET1 or TET3 knockdown significantly reduced 5-hmC levels in leiomyoma cells and decreased cell proliferation. Treatment with 2-hydroxyglutarate, a competitive TET enzyme inhibitor, significantly decreased both 5-hmC content and cell proliferation of leiomyoma cells.

Conclusion: An epigenetic imbalance in the 5-hmC content of leiomyoma tissue, caused by upregulation of the TET1 and TET3 enzymes, might lead to discovery of new therapeutic targets in leiomyoma.

Original languageEnglish (US)
Pages (from-to)E2437-E2445
JournalJournal of Clinical Endocrinology and Metabolism
Volume99
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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