Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells.
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.
Yin
Ping
P
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine at Northwestern University, Chicago, IL 60611, USA.
Lin
Zhihong
Z
Reierstad
Scott
S
Wu
Ju
J
Ishikawa
Hiroshi
H
Marsh
Erica E
EE
Innes
Joy
J
Cheng
Youhong
Y
Pearson
Kerry
K
Coon
John Sayler
JS
Kim
J Julie
JJ
Chakravarti
Debabrata
D
Bulun
Serdar E
SE
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D015735:Mifepristone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D047368:Tumor Burden / Q000235:genetics; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D006727:Hormone Antagonists; C115117:KLF11 protein, human; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D015735:Mifepristone; D011374:Progesterone