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

Abstract

Summary 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.

Epigenetic Regulation in Uterine Fibroids—The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application

“…In UF stem cells, genes crucial for their differentiation were hypermethylated [ 50 ]. Furthermore, a recently published paper confirmed that the differentiation process of UF stem cells is linked to both progesterone signaling and DNA methylation [ 35 ]. In UF stem cells, endometrial cancer and endometriosis PR expression was inhibited due to the hypermethylation of the PR gene [ 40 , 51 ].…”

“…Conversely, ESR1 expression in uterine cells is inhibited by progesterone through PR [ 34 ]. Additionally, there are several tissue-specific methylation sites around the PR locus [ 35 ].…”

“…Progesterone receptor gene hypermethylation results in decreased expression of genes critical for progesterone-induced UF stem cell differentiation. PR knockdown was associated with increased global DNA methylation by regulating TET enzymes [ 35 ].…”

“…Several studies also demonstrated an effect of demethylating agents on UFs. Treatment of a xenograft mouse model with both 5′-Aza, and an antiprogestational agent (mifepristone) resulted in an almost complete reduction in UF tumors [ 35 ]. Therefore, 5’-Aza, may activate PR signaling, and stimulate differentiation of UF stem cells to reduce tumor size in vivo.…”

Progesterone Actions and Resistance in Gynecological Disorders

“…Furthermore, MED12 mutation, especially at G44D, further stabilizes PGR binding at the regulator element of RANKL, indicating that a complex network constituted by DNA methylation and MED12 mutations regulates the progesterone-mediated RANKL gene expression contributing to leiomyoma tumor development [ 204 ]. This group has further reported that the PGR gene locus and its genome-wide cistrome are hypermethylated in leiomyoma stem cells, repressing the expression of genes for progesterone-mediated leiomyoma stem cell differentiation [ 205 ].…”