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.

子宫肌瘤（LM）是女性最常见的肿瘤。黄体酮通过在分化的 LM 细胞中表达的受体 (PGR) 刺激旁分泌信号，从而诱导 PGR 缺陷的 LM 干细胞 (LSC) 的增殖。抗孕激素可使 LM 缩小，但治疗停止后肿瘤会重新生长，这可能是由于 LSC 持续存在所致。使用分选的原代LM细胞群，我们发现LSC中的PGR基因位点及其目标顺反子高度甲基化，抑制对黄体酮诱导LSC分化至关重要的基因的表达。PGR 敲低将总 LM 细胞的转录组转向 LSC，并通过调节 TET 甲基胞嘧啶双加氧酶增加整体 DNA 甲基化。DNA 甲基化抑制剂 5'-Aza 激活 PGR 信号传导，刺激 LSC 分化，并与抗孕激素协同作用以减小体内肿瘤大小。总而言之，针对 DNA 甲基化和黄体酮信号传导之间的反馈环路可能会通过快速分化加速 LSC 的消耗，并使 LM 对抗孕激素治疗敏感，从而防止肿瘤再生。