Krüppel-like transcription factor 11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells

摘要

Uterine leiomyoma is the most common tumor of the female genital tract and the leading cause of hysterectomy. While progesterone stimulates 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 down-regulated by progesterone but robustly up-regulated by the progesterone antagonist RU486. Luciferase reporter assays demonstrated 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, while knockdown of KLF11 increased leiomyoma cell proliferation and abolished the anti-proliferative 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.