Targeting DNA Methylation Depletes Uterine Leiomyoma Stem Cell-enriched Population by Stimulating Their Differentiation.

Abstract

Uterine leiomyoma (LM) is the most common tumor in women and can cause severe morbidity. Leiomyoma growth requires the maintenance and proliferation of a stem cell population. Dysregulated deoxyribonucleic acid (DNA) methylation has been reported in LM, but its role in LM stem cell regulation remains unclear. Here, we fluorescence-activated cell sorting (FACS)-sorted cells from human LM tissues into 3 populations: LM stem cell-like cells (LSC, 5%), LM intermediate cells (LIC, 7%), and differentiated LM cells (LDC, 88%), and we analyzed the transcriptome and epigenetic landscape of LM cells at different differentiation stages. Leiomyoma stem cell-like cells harbored a unique methylome, with 8862 differentially methylated regions compared to LIC and 9444 compared to LDC, most of which were hypermethylated. Consistent with global hypermethylation, transcript levels of TET1 and TET3 methylcytosine dioxygenases were lower in LSC. Integrative analyses revealed an inverse relationship between methylation and gene expression changes during LSC differentiation. In LSC, hypermethylation suppressed the genes important for myometrium- and LM-associated functions, including muscle contraction and hormone action, to maintain stemness. The hypomethylating drug, 5'-Aza, stimulated LSC differentiation, depleting the stem cell population and inhibiting tumor initiation. Our data suggest that DNA methylation maintains the pool of LSC, which is critical for the regeneration of LM tumors.

• Authors: Shimeng Liu, Ping Yin, Jingting Xu, Ariel J Dotts, Stacy A Kujawa, John S Coon V, Hong Zhao, Ali Shilatifard, Yang Dai, Serdar E Bulun
• Journal: Endocrinology (Endocrinology) Vol. 161 Issue 10 (Oct 01 2020) ISSN: 1945-7170 [Electronic] United States
• PMID: 32812024 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © Endocrine Society 2020.

Chemical References

• Mifepristone
• Azacitidine

Topics

• Adult
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Azacitidine (administration & dosage, pharmacology)
• Cell Count
• Cell Differentiation (drug effects)
• Cells, Cultured
• DNA Methylation (drug effects)
• Female
• Humans
• Leiomyoma (drug therapy, pathology)
• Mice
• Mice, SCID
• Mice, Transgenic
• Middle Aged
• Mifepristone (administration & dosage, pharmacology)
• Molecular Targeted Therapy
• Neoplastic Stem Cells (drug effects, pathology, physiology)
• Uterine Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays