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Progesterone receptor-DNA methylation crosstalk regulates depletion of uterine leiomyoma stem cells: A potential therapeutic target.
- Source :
-
Stem cell reports [Stem Cell Reports] 2021 Sep 14; Vol. 16 (9), pp. 2099-2106. Date of Electronic Publication: 2021 Aug 12. - Publication Year :
- 2021
-
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.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Binding Sites
Consensus Sequence
Down-Regulation
Humans
Immunophenotyping
Leiomyoma drug therapy
Leiomyoma metabolism
Leiomyoma pathology
Models, Biological
Nucleotide Motifs
Protein Binding
Receptors, Progesterone metabolism
Biomarkers, Tumor
DNA Methylation drug effects
Gene Expression Regulation, Neoplastic drug effects
Leiomyoma etiology
Neoplastic Stem Cells metabolism
Receptors, Progesterone genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2213-6711
- Volume :
- 16
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Stem cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 34388365
- Full Text :
- https://doi.org/10.1016/j.stemcr.2021.07.013