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Project description:Uterine leiomyomas (UL) are benign tumors that arise in the myometrial layer of the uterus. The standard treatment option for UL is hysterectomy, although hormonal therapies, such as selective progesterone receptor modulators, are often used as temporary treatment options to reduce symptoms or to slow the growth of tumors. However, since the pathogenesis of UL is poorly understood and most hormonal therapies are not based on UL-specific, divergent hormone signaling pathways, hallmarks that predict long-term efficacy and safety of pharmacotherapies remain largely undefined. In a previous study, we reported that aberrant expression of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes activate UL growth due to the near ubiquitous loss of REST. Here, we show that ablation of the Rest gene in mouse uterus leads to UL phenotype and gene-expression patterns analogous to UL, including altered estrogen and progesterone signaling pathways. We demonstrate that many of the genes dysregulated in UL harbor cis-regulatory elements bound by REST and progesterone receptor (PGR) adjacent to each other. Crucially, we identify an interaction between REST and PGR in healthy myometrium and present a putative mechanism for the dysregulation of progesterone-responsive genes in UL ensuing in the loss of REST. Using three Rest conditional knockout mouse lines, we provide a comprehensive picture of the impact loss of REST has in UL pathogenesis and in altering the response of UL to steroid hormones.
| S-EPMC9636955 | biostudies-literature
Project description:Uterine Leiomyomas (UL) are benign tumors that arise in the myometrium of the uterus. The standard treatment option for UL is hysterectomy but hormonal treatment options are emerging in the field. However, since the pathogenesis of UL is poorly understood, hallmarks that predict long-term efficacy and safety of these treatment options remain largely undefined. We have reported previously that REST/NRSF target genes are aberrantly expressed due to the near ubiquitous loss of this epigenetic repressor in UL tumors. We show that ablation of Rest in the mouse uterus leads to UL phenotype and altered response to steroid hormones estrogen and progesterone. Additionally, we demonstrate that a large number of REST target genes dysregulated in UL as well as in Rest cKO mice, are also targets of progesterone receptor (PR). Importantly, we identify a direct interaction between REST and PR in the healthy myometrium. Rest cKO mouse model phenocopies human UL, including gene expression profiles of UL as well as tumor formation in the myometrium. Our findings emphasize the critical role loss of REST plays in disease pathogenesis and the altered response to steroid hormones seen in UL.
2022-10-12 | GSE178140 | GEO
Project description:Uterine Leiomyomas (UL) are benign tumors that arise in the myometrium of the uterus. The standard treatment option for UL is hysterectomy but hormonal treatment options are emerging in the field. However, since the pathogenesis of UL is poorly understood, hallmarks that predict long-term efficacy and safety of these treatment options remain largely undefined. We have reported previously that REST/NRSF target genes are aberrantly expressed due to the near ubiquitous loss of this epigenetic repressor in UL tumors. We show that ablation of Rest in the mouse uterus leads to UL phenotype and altered response to steroid hormones estrogen and progesterone. Additionally, we demonstrate that a large number of REST target genes dysregulated in UL as well as in Rest cKO mice, are also targets of progesterone receptor (PR). Importantly, we identify a direct interaction between REST and PR in the healthy myometrium. Rest cKO mouse model phenocopies human UL, including gene expression profiles of UL as well as tumor formation in the myometrium. Our findings emphasize the critical role loss of REST plays in disease pathogenesis and the altered response to steroid hormones seen in UL.
2022-10-12 | GSE178086 | GEO
Project description:Loss of the repressor REST affects progesterone receptor function and promotes uterine leiomyoma pathogenesis
| PRJNA737445 | ENA
Project description:Loss of the repressor REST affects progesterone receptor function and promotes uterine leiomyoma pathogenesis [scRNA-seq]
| PRJNA737342 | ENA
Project description:Loss of the repressor REST affects progesterone receptor function and promotes uterine leiomyoma pathogenesis [RNA-seq]
| PRJNA737452 | ENA
Project description:Uterine leiomyoma is the most common tumor of the female genital tract and the leading cause of hysterectomy. Although progesterone stimulates the proliferation of uterine leiomyoma cells, the mechanism of progesterone action is not well understood. We used chromatin immunoprecipitation (ChIP)-cloning approach to identify progesterone receptor (PR) target genes in primary uterine leiomyoma smooth muscle cells. We identified 18 novel PR-binding sites, one of which was located 20.5 kb upstream of the transcriptional start site of the Krüppel-like transcription factor 11 (KLF11) gene. KLF11 mRNA levels were minimally downregulated by progesterone but robustly upregulated by the progesterone antagonist RU486. Luciferase reporter assays showed significant baseline and RU486-inducible promoter activity in the KLF11 basal promoter or distal PR-binding region, both of which contained multiple Sp1-binding sequences but lacked classic progesterone response elements. RU486 stimulated recruitment of Sp1, RNA polymerase II, PR, and the coactivators SRC-1 and SRC-2 to the distal region and basal promoter. siRNA knockdown of PR increased KLF11 expression, whereas knockdown of KLF11 increased leiomyoma cell proliferation and abolished the antiproliferative effect of RU486. In vivo, KLF11 expression was significantly lower in leiomyoma tissues compared with adjacent myometrial tissues. Taken together, using a ChIP-cloning approach, we uncovered KLF11 as an integrator of PR signaling and proliferation in uterine leiomyoma cells.
| S-EPMC2822899 | biostudies-literature
Project description:Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.
| S-EPMC2875812 | biostudies-literature
Project description: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.
| S-EPMC8452515 | biostudies-literature
Project description:Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor/neuron-restrictive silencing factor (REST/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.
| S-EPMC3568308 | biostudies-literature