Estrogen regulates tumor growth through a nonclassical pathway that includes the transcription factors ERβ and KLF5

Yuka Nakajima, Kensuke Akaogi, Takashi Suzuki, Asami Osakabe, Chie Yamaguchi, Nanae Sunahara, Junji Ishida, Koichiro Kako, Sonoko Ogawa, Tetsuya Fujimura, Yukio Homma, Akiyoshi Fukamizu, Akiko Murayama, Keiji Kimura, Satoshi Inoue, Junn Yanagisawa

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Clinical evidence suggests that antiestrogens inhibit the development of androgen-insensitive prostate cancer. Here, we show that the estrogen receptor β (ERβ) mediates inhibition by the antiestrogen ICI 182,780 (ICI) and its enhancement by estrogen. ERβ associated with gene promoters through the tumor-suppressing transcription factor KLF5 (Krüppel-like zinc finger transcription factor 5). ICI treatment increased the recruitment of the transcription coactivator CBP [CREB (adenosine 3′,5′-monophosphate response element-binding protein)-binding protein] to the promoter of FOXO1 through ERβ and KLF5, which enhanced the transcription of FOXO1. The increase in FOXO1 abundance led to anoikis in prostate cancer cells, thereby suppressing tumor growth. In contrast, estrogen induced the formation of complexes containing ERβ, KLF5, and the ubiquitin ligase WWP1 (WW domain containing E3 ubiquitin protein ligase 1), resulting in the ubiquitination and degradation of KLF5. The combined presence of KLF5 and ERβ positively correlated with longer cancer-specific survival in prostate cancer patients. Our results demonstrate that estrogens and antiestrogens affect prostate tumor growth through ERβ-mediated regulation of KLF5.

Original languageEnglish
Article numberra22
JournalScience Signaling
Volume4
Issue number168
DOIs
Publication statusPublished - 2011 Apr 12
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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