Progesterone receptor-DNA methylation crosstalk regulates depletion of uterine leiomyoma stem cells: A potential therapeutic target

Shimeng Liu, Ping Yin, Jingting Xu, Ariel J. Dotts, Stacy A. Kujawa, John S. Coon V, Hong Zhao, Yang Dai, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Uterine leiomyoma (LM) is the most common tumor in women. Via its receptor (PGR) expressed in differentiated LM cells, progesterone stimulates paracrine signaling that induces proliferation of PGR-deficient LM stem cells (LSCs). Antiprogestins shrink LM but tumors regrow after treatment cessation possibly due to persisting LSCs. Using sorted primary LM cell populations, we found that the PGR gene locus and its target cistrome are hypermethylated in LSCs, inhibiting the expression of genes critical for progesterone-induced LSC differentiation. PGR knockdown shifted the transcriptome of total LM cells toward LSCs and increased global DNA methylation by regulating TET methylcytosine dioxygenases. DNA methylation inhibitor 5′-Aza activated PGR signaling, stimulated LSC differentiation, and synergized with antiprogestin to reduce tumor size in vivo. Taken together, targeting the feedback loop between DNA methylation and progesterone signaling may accelerate the depletion of LSCs through rapid differentiation and sensitize LM to antiprogestin therapy, thus preventing tumor regrowth.

Original languageEnglish (US)
Pages (from-to)2099-2106
Number of pages8
JournalStem cell reports
Volume16
Issue number9
DOIs
StatePublished - Sep 14 2021

Keywords

  • DNA methylation
  • progesterone receptor
  • stem cell regulation
  • uterine leiomyoma

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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