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 language | English (US) |
|---|---|
| Pages (from-to) | 2099-2106 |
| Number of pages | 8 |
| Journal | Stem cell reports |
| Volume | 16 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 14 2021 |
Funding
We acknowledge the Northwestern University Flow Cytometry Facility, NUSeq Core, and Pathology Core Facility, which are co-funded by a National Cancer Institute Cancer Center grant CA060553. Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01. This work was supported by the National Institutes of Health grants P01-HD057877 and P50-HD098580 (to S.E.B. and P.Y.). We acknowledge the Northwestern University Flow Cytometry Facility, NUSeq Core, and Pathology Core Facility, which are co-funded by a National Cancer Institute Cancer Center grant CA060553 . Flow Cytometry Cell Sorting was performed on a BD FACSAria SORP system, purchased through the support of NIH 1S10OD011996-01 . This work was supported by the National Institutes of Health grants P01-HD057877 and P50-HD098580 (to S.E.B. and P.Y.).
Keywords
- DNA methylation
- progesterone receptor
- stem cell regulation
- uterine leiomyoma
ASJC Scopus subject areas
- Biochemistry
- Genetics
- Developmental Biology
- Cell Biology
